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United States Government Accountability Office:
GAO:
Report to Congressional Requesters:
November 2011:
Drug Shortages:
FDA's Ability to Respond Should Be Strengthened:
GAO-12-116:
GAO Highlights:
Highlights of GAO-12-116, a report to congressional requesters.
Why GAO Did This Study:
In recent years, nationwide shortages of prescription drugs have
increased, preventing patients from accessing medications essential to
their care. The Food and Drug Administration (FDA), an agency within
the Department of Health and Human Services (HHS), established a Drug
Shortage Program with a mission of helping to prevent, alleviate, and
resolve shortages. FDA receives information about shortages from
manufacturers, though this reporting is generally voluntary, as well
as from the American Society of Health-System Pharmacists (ASHP). ASHP
tracks nationwide shortages for its members through a partnership with
the University of Utah Drug Information Service (UUDIS).
GAO was asked to review trends in shortages and examine FDA’s
response. In this report, GAO (1) reviews trends in drug shortages,
(2) describes FDA’s response, and (3) evaluates FDA’s ability to
protect public health through its response to drug shortages. GAO
analyzed UUDIS data, interviewed officials from FDA, health care
professional associations, and industry, and also examined relevant
statutes, regulations, information, and documents.
What GAO Found:
The number of drug shortages has grown substantially since 2006. In
total, 1,190 shortages were reported from January 1, 2001, through
June 20, 2011, according to UUDIS data. From 2006 through 2010, the
number of drug shortages increased each year. A record number of
shortages were reported in 2010, and 2011 is on pace to surpass 2010’s
record. Sixty-four percent of shortages involved drugs that were in
short supply more than once. On average, shortages lasted 286 days
(over 9 months). Over half of shortages reported from January 1, 2009,
through June 20, 2011, that UUDIS identified as critical-—because, for
example, alternative drugs were not available-—involved generic
injectable drugs. Certain therapeutic classes (such as anesthetic,
oncology, and anti-infective drugs) were among those most often in
short supply.
Figure: Drug Shortages Reported January 1, 2001 through June 20, 2011,
by Year:
[Refer to PDF for image: vertical bar graph]
Year: 2001;
Number of drug shortages reported: 103.
Year: 2002;
Number of drug shortages reported: 80.
Year: 2003;
Number of drug shortages reported: 71.
Year: 2004;
Number of drug shortages reported: 54.
Year: 2005;
Number of drug shortages reported: 71.
Year: 2006;
Number of drug shortages reported: 64.
Year: 2007;
Number of drug shortages reported: 114.
Year: 2008;
Number of drug shortages reported: 138.
Year: 2009;
Number of drug shortages reported: 153.
Year: 2010;
Number of drug shortages reported: 196.
Year: 2011;
Number of drug shortages reported: 148 (shortages reported through
June 20).
Source: GAO analysis of University of Utah Drug Information Service
data.
[End of figure]
FDA responds to drug shortages by taking actions to address the
underlying causes and to enhance product availability, for example by
providing assistance to manufacturers to resolve manufacturing or
quality problems that can result in a shortage. When informed of the
possibility of a shortage in advance, FDA has increasingly been able
to prevent potential drug shortages from occurring. FDA prevented 50
potential shortages during the first half of 2011. As part of its
response, FDA provides general information about drug shortages to the
public via its website.
FDA is constrained in its ability to protect public health from drug
shortages due to its lack of authority to require manufacturers to
report actual or potential shortages to the agency or the public, or
to require manufacturers to take certain actions to prevent,
alleviate, or resolve shortages. As a result, the agency’s approach to
managing drug shortages is predominately reactive. FDA’s ability to
protect public health is also constrained by management challenges
that weaken its ability to respond to drug shortages. For example, FDA
does not systematically maintain data on drug shortages, without which
it is unable to monitor trends and enhance its ability to address the
causes of drug shortages. In addition, FDA has provided limited
resources to manage its response to drug shortages and lacks related
performance measures and priorities.
What GAO Recommends:
Congress should consider establishing a requirement for manufacturers
to report to FDA any changes that could affect the supply of their
drugs. In addition, FDA should enhance its ability to respond to drug
shortages, for example, by developing an information system to manage
data about shortages. HHS outlined actions it plans to take that are
consistent with GAO’s recommendations.
View [hyperlink, http://www.gao.gov/products/GAO-12-116] or key
components. For more information, contact Marcia Crosse at (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
The Number of Drug Shortages Has Grown Substantially Since 2006, and
Many Involved Generic Injectable Drugs:
Drug Shortages We Reviewed Were Generally Caused by Manufacturing
Problems and Exacerbated by Multiple Difficulties:
Actions Taken by FDA to Respond to Drug Shortages Are Intended to
Resolve Shortages' Underlying Causes and Enhance Product Availability:
FDA Is Constrained in Its Ability to Protect Public Health from Drug
Shortages:
Conclusions:
Matter for Congressional Consideration:
Recommendations for Executive Action:
Agency and Third-Party Comments and Our Evaluation:
Appendix I: FDA Criteria for Determining Whether a Drug Is Medically
Necessary:
Appendix II: Summary of FDA's Response to 15 Selected Drug Shortages:
Appendix III: Comments from the Department of Health and Human
Services:
Appendix IV: GAO Contact and Staff Acknowledgments:
Related GAO Products:
Tables:
Table 1: Summary of the Duration of Drug Shortages, January 1, 2001,
through June 20, 2011, by Shortage Status:
Table 2: Summary of 269 Critical Drug Shortages Reported January 1,
2009, through June 20, 2011, by Product Type:
Table 3: Summary of 269 Critical Drug Shortages Reported January 1,
2009, through June 20, 2011, by Route of Administration:
Table 4: Summary of 269 Critical Drug Shortages Reported January 1,
2009, through June 20, 2011, by Therapeutic Class:
Table 5: Summary of Difficulties That Subsequently Exacerbated 15
Sterile Injectable Drug Shortages That Occurred Between January 2009
and June 2011:
Table 6: Summary of Actions Taken by FDA in Response to 15 Shortages
of Sterile Injectable Drugs That Occurred Between January 2009 and
June 2011:
Table 7: Actions Taken by FDA to Prevent Potential Drug Shortages,
2010 and 2011, through June:
Figures:
Figure 1: Number of Drug Shortages Reported January 1, 2001, through
June 20, 2011, by Year:
Figure 2: Distribution of the Duration of Reported Drug Shortages,
January 1, 2001, through June 20, 2011:
Figure 3: Distribution of 269 Critical Drug Shortages Reported January
1, 2009, through June 20, 2011, by Product Type and Route of
Administration:
Figure 4: Summary of Primary Causes of 15 Sterile Injectable Drug
Shortages That Occurred Between January 2009 and June 2011:
Figure 5: Questions Included on FDA's Medical Necessity Determination
Form:
Figure 6: Actions Taken by FDA in Response to Sterile Injectable Drug
Shortages That Were Reported Between January 2009 and June 2011, by
Drug Class and Name:
Abbreviations:
ANDA: abbreviated new drug application:
API: active pharmaceutical ingredient:
ASA: American Society of Anesthesiologists:
ASCO: American Society of Clinical Oncology:
ASHP: American Society of Health-System Pharmacists:
CDER: Center for Drug Evaluation and Research:
CNS: central nervous system:
FDA: Food and Drug Administration:
HHS: Department of Health and Human Services:
IDSA: Infectious Diseases Society of America:
NDA: new drug application:
NDC: national drug code:
OGD: Office of Generic Drugs:
OND: Office of New Drugs:
UUDIS: University of Utah Drug Information Service:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
November 21, 2011:
The Honorable Tom Harkin:
Chairman:
Committee on Health, Education, Labor, and Pensions:
United States Senate:
The Honorable Richard Blumenthal:
United States Senate:
The Honorable Robert P. Casey, Jr.
United States Senate:
In recent years, hospitals and health care professionals have
increasingly reported nationwide shortages of prescription drugs,
including those that are life-saving and life-sustaining. Drug
shortages directly threaten public health by preventing patients from
accessing medications that are essential to their care. For example,
recent shortages of oncology drugs have sparked concerns from health
care professionals about how to care for cancer patients that need
such medications in order to survive. During shortages, physicians may
have to ration their supplies, delay treatments, or use alternative
medications that may be less effective for the condition, carry
unwanted side effects, or are more costly.
The Food and Drug Administration (FDA)--an agency within the
Department of Health and Human Services (HHS) that is responsible for
overseeing the safety and effectiveness of drugs marketed in the
United States--has recognized the significant public health
consequences that can result from drug shortages. According to FDA, a
record number of drugs were in short supply in 2010, and the number of
drug shortages continued to grow during 2011. Consistent with its
mission of protecting the public health, FDA established its Drug
Shortage Program in 1999 out of growing concern over the increasing
number of drug shortages. The purpose of this program is to help
prevent, alleviate, and resolve shortage situations. To do this, FDA
must identify and monitor potential and actual drug shortages, which
may be reported to the agency by manufacturers, health professionals,
and the public. To develop more comprehensive information on drug
shortages, FDA also obtains information from the American Society of
Health-System Pharmacists (ASHP). ASHP began tracking data on drug
shortages--in partnership with the University of Utah Drug Information
Service (UUDIS)--in 2001 to inform its members, such as hospital
pharmacists, and the public about the status of new, ongoing, and
resolved shortages.[Footnote 1]
You asked us to examine issues related to the causes of prescription
drug shortages and FDA's response to these shortages. This report (1)
reviews trends in prescription drug shortages that occurred from
January 2001 through June 2011, (2) identifies the reported causes of
selected drug shortages that occurred from January 2009 through June
2011, (3) describes FDA's response to drug shortages, and (4)
evaluates the extent to which FDA is able to protect the public health
through its response to drug shortages.
To review trends in prescription drug shortages that occurred from
January 2001 through June 2011, we analyzed UUDIS data on the number
of shortages reported to ASHP during that time period, through June
20, 2011. We examined these data because FDA did not have a database
containing information on drug shortages for the time period we
reviewed, and UUDIS is generally regarded as the most comprehensive
and reliable source of such information. We reviewed UUDIS data to
determine the number of shortages of prescription drugs that were
identified each year and the duration of these shortages.[Footnote 2]
To identify the number of drugs that had been in short supply on
multiple occasions and the collective duration of these shortages, we
grouped together shortages that involved clinically interchangeable
versions of a drug that is administered through the same route--for
example, by injection. We confirmed our identification of clinically
interchangeable versions of a drug with a knowledgeable UUDIS
pharmacist. We also examined the characteristics of 269 critical drug
shortages that were identified during a shorter time period, January
1, 2009, through June 20, 2011.[Footnote 3] UUDIS recognized these
shortages as critical because alternative medications were
unavailable, the shortages affected multiple manufacturers, or the
shortages were widely reported, and because the shortages were
determined to be critical, they were posted to ASHP's website. We
obtained from UUDIS the national drug codes (NDC) that were associated
with each of these critical shortages; UUDIS does not consistently
track the NDCs associated with shortages that it determines are not
critical.[Footnote 4] Using these NDCs, we analyzed Red Book data to
determine the routes of administration, therapeutic classes, and
number of manufacturers associated with each shortage.[Footnote 5] To
obtain context for the trends we identified, we interviewed officials
at FDA, UUDIS, and ASHP. We also discussed the data with knowledgeable
officials at UUDIS, and we reviewed all data for reasonableness,
outliers, and consistency; we determined that the data were
sufficiently reliable for our purposes.
To identify the reported causes of selected drug shortages that
occurred from January 2009 through June 2011, we focused our analysis
on a nongeneralizable sample of 15 drug shortages that have had a
significant impact on public health. The drugs involved in these
shortages--all sterile injectables--are from three therapeutic
classes: anesthesia, oncology, and anti-infective drugs. To assist in
the selection of shortages for our detailed review, we asked
representatives from the American Society of Anesthesiologists (ASA),
the American Society of Clinical Oncology (ASCO), and the Infectious
Diseases Society of America (IDSA) to each identify 5 shortages of
sterile injectable drugs that were specific to their members' practice
areas, that occurred from January 2009 through June 2011, and that had
a significant impact on patient care or public health. Our analysis
reflects the 15 drug shortages suggested by these associations.
[Footnote 6] We asked FDA officials to provide information on the
causes of these 15 drug shortages, as reported by manufacturers. Using
the information FDA provided, we determined the first event that
resulted in the shortage. We also captured information on other events
that affected the availability of the drug before the shortage was
resolved. For additional information on the causes of shortages, we
obtained information from four manufacturers of sterile injectable
drugs--APP Pharmaceuticals, Bedford Laboratories, Hospira, and Teva
Pharmaceuticals. All of these manufacturers produce drugs that
recently were in short supply, and all of the 15 drug shortages we
selected for review involved drugs that were manufactured by one or
more of these manufacturers. The results of our review of the 15 drug
shortages are not generalizable to other drug shortages.
To describe FDA's response to drug shortages, we interviewed FDA
officials and reviewed agency documents, including policies and
procedures.[Footnote 7] To describe how FDA responded to the 15
selected drug shortages we reviewed in detail, we examined information
the agency provided about its response to these shortages. We also
analyzed FDA information on potential drug shortages the agency
prevented from January 2010 through June 2011. To determine the number
of shortages prevented, we grouped together shortages that involved
multiple versions of a drug that had the same route of administration.
To evaluate the extent to which FDA is able to protect public health
through its response to drug shortages, we analyzed FDA's authority
under the Federal Food, Drug, and Cosmetic Act. We also examined
relevant FDA regulations, policies, and procedures, and reviewed FDA's
strategic priorities regarding drug availability. We evaluated FDA's
approach to managing its response to drug shortages using standards
for internal control--including those for information and
communications, monitoring, and risk assessment.[Footnote 8] In
addition, we considered information in our previous reports on
strategic planning, workforce planning, and the establishment of
results-oriented performance measures. We also obtained the health
care community's perspective on FDA's response to, and communication
about, drug shortages by interviewing officials from ASA, ASCO, ASHP,
IDSA, and the Institute for Safe Medication Practices. To obtain drug
manufacturers' perspective on FDA's response to shortages, we
interviewed officials from the four manufacturers of generic drugs
noted above, as well as officials from the Generic Pharmaceutical
Association, the Pharmaceutical Research and Manufacturers of America,
and the Biotechnology Industry Organization. We also interviewed
officials from Premier Healthcare Alliance, a group purchasing
organization, the Healthcare Distribution Management Association, and
the United States Pharmacopoeia to obtain the perspective of other
stakeholders involved in drug production and the drug supply chain.
We conducted this performance audit from June 2011 to October 2011 in
accordance with generally accepted government auditing standards.
Those standards require that we plan and perform the audit to obtain
sufficient, appropriate evidence to provide a reasonable basis for our
findings and conclusions based on our audit objectives. We believe
that the evidence obtained provides a reasonable basis for our
findings and conclusions based on our audit objectives.
Background:
The unavailability of drugs can result in problems that directly
affect the public health and increase costs for providers and
patients. FDA's role in overseeing the safety and effectiveness of
drugs provides the agency an opportunity to take actions to prevent,
alleviate, and resolve drug shortages.
Factors Affecting Drug Availability:
A variety of factors can trigger drug availability problems. These
factors can involve any segment of the supply chain, from problems
related to the growth or harvest of ingredients required to
manufacture a drug, to increased demand for products by consumers or
providers.[Footnote 9] They include the following:
* Disruption in the supply of raw materials. Manufacturers are
sometimes unable to obtain the raw materials used in producing a drug,
including the active pharmaceutical ingredients (API) and inactive
ingredients.[Footnote 10] APIs may become in short supply as a result
of climactic or environmental changes that depress the growth of
plants from which the materials are extracted, or the APIs could be
contaminated or degraded during harvesting, storage, or transport. API
manufacturers may encounter problems synthesizing the chemical
components of an API or face shortages of their ingredients. Finally,
firms involved in the harvest, manufacture, storage, or transport of
these materials could decide to exit the market, which could affect
the availability of these materials for the manufacture of finished
drug products. According to FDA, the majority of APIs used in FDA-
approved drugs are imported from foreign countries, which may add to
challenges related to their availability. For example, regulations
issued by foreign countries regarding the use or export of these
materials could affect their availability. In addition, APIs may be
held for examination during the importation process, delaying their
availability.
* Manufacturing problems. Manufacturers may have problems producing a
finished drug that is safe, pure, and of high quality. Manufacturers
may identify these problems themselves, or FDA may identify them
during an inspection. Regardless of how the problems are identified, a
manufacturer may voluntarily decide to stop producing a drug until the
problem can be resolved. In addition, the manufacturer may decide to
recall a drug in order to remove it from the market.[Footnote 11]
* Manufacturers' business decisions. Manufacturers' business decisions
may affect the production and supply of a drug. For example, a
manufacturer may decide to discontinue its production of a drug as a
result of decreased profitability. Or, a manufacturer may decide to
renovate a facility, requiring a temporary shutdown of production.
* Industry consolidations. Recent mergers and acquisitions within the
drug industry have reduced the number of manufacturers making drugs.
Many drugs that have recently been in short supply are only produced
by a few manufacturers. As the number of manufacturers of a product
decreases, there is an increased likelihood that a problem with one
manufacturer will lead to a shortage of all versions of that drug. For
example, if only three manufacturers make a drug and one manufacturer
halts production, it is often difficult--if not impossible--for the
remaining two manufacturers to increase their production enough to
meet consumer demand.
* Unexpected increase in demand. A shortage may occur due to
unexpected shifts in demand caused, for example, by a change in the
clinical use of a product or due to a shortage of a similar drug.
Shortages may also occur when hospitals or other health care providers
stockpile particular drugs to take advantage of low prices, by placing
orders that exceed normal demand.[Footnote 12]
* Natural disasters. Natural disasters can create drug shortages when
they affect the supply of raw materials or manufacturing facilities.
* Unstable supply chain. An increasingly unstable supply chain for
drugs also contributes to drug shortages. Recent changes in supply
chain management have increased the cost-effectiveness of individual
participants in the supply chain, but have also resulted in a
reduction in individual participants' capacity to respond to supply
disruptions. Factors that impact the availability of drugs in the
supply chain include the complex nature of the global supply chain,
reduced manufacturing capacity, and lean inventory systems.
- Complex, global supply chain. The supply chain for drugs is highly
complex, increasingly global, and involves a large number of
organizations that are highly dependent on each other. Manufacturers
of finished drug products rely on an increasingly global supply chain
in which each manufacturing step may be outsourced to foreign
establishments.[Footnote 13] For example, manufacturers of finished
drug products are dependent on manufacturers of active and inactive
ingredients as well as the distribution of those products to the
manufacturing site where the finished drug is produced. As a result of
the large numbers of entities involved in the supply chain, every
individual member of the chain has less control, and is less able to
respond to problems experienced by those on which it is dependent.
- Manufacturing capacity constraints. Some companies may have reduced
manufacturing redundancies to save on costs--for example, by cutting
back on the number of their manufacturing facilities, or the number of
manufacturing lines available to produce certain drugs. These changes
reduce the manufacturer's capacity to respond to its own manufacturing
problems. In addition, some companies produce multiple drugs using the
same manufacturing line. If a problem occurs with the manufacturing
line, it can affect the production of all drugs made on that line.
- Lean inventory systems. Manufacturers, distributors, hospitals, and
other health care providers have been increasingly using leaner "just-
in-time" inventory systems that allow them to maintain smaller
inventories of drugs at any given time. Many providers have reduced on-
hand inventories to the extent that they are dependent on daily
replenishments from suppliers. As a result, all parts of the supply
chain are more likely to feel the effects of a shortage more quickly.
Potential Effects of Drug Shortages:
Shortages of drugs can result in a variety of problems, ranging from
those that directly affect patient care to those that increase costs
for providers and patients. These include the following:
* Delays in patient care. Some shortages result in situations where a
viable alternative drug is not available, and a patient may be unable
to receive treatment. Some hospitals and ambulatory surgery centers
have been forced to postpone surgeries due to a shortage of anesthetic
drugs.[Footnote 14] A lack of treatment can have serious consequences.
For example, a recent shortage of anti-infective drugs contributed to
patient deaths from infections that were only treatable by drugs that
were in short supply.
* Ethical dilemmas. When drugs are in short supply, providers may be
unable to obtain needed drugs to treat all of their patients. They may
therefore have to make difficult choices, such as deciding which
cancer patients should start or complete a round of chemotherapy.
* Treatment with less effective alternative drugs. Alternative drugs
may be able to treat some patients. However, some alternative
treatments may provide a lower rate of effectiveness and a higher
likelihood of adverse events.
* Medication errors. Drug shortages can result in the need to treat
patients with unfamiliar drugs, for example, different drugs, or the
same drug that is available in a different strength. Administering
such products can result in medication errors.[Footnote 15]
* Increased costs for providers and patients. Shortages require time
and resources to manage. Health care providers need to determine how
to obtain the drug in short supply, or staff must spend time searching
for available treatment options. In addition, the use of alternative
medications can result in the need for additional training. In order
to learn how to avoid medication errors, health care providers need to
learn how to accurately prescribe and administer the alternative
products, with which they may lack familiarity. Finally, the cost of
the drug in short supply--or available alternative--may be higher than
usual.[Footnote 16]
* Use of the gray market. Providers who are unable to obtain drugs
from their regular distributors may resort to purchasing drugs from
distribution channels that were not authorized by the manufacturer,
referred to as the gray market.[Footnote 17] Gray market suppliers
typically obtain small quantities of a drug that is in short supply
and offer it for purchase to others at an inflated price.[Footnote 18]
Because the origin of gray market drugs may be unknown, there is no
guarantee of the drug's pedigree or assurance that it was stored and
transported appropriately. As a result, patients who receive treatment
with such drugs may experience adverse events or receive inadequate or
inappropriate treatment.[Footnote 19]
* Unauthorized use of compounding pharmacies. In some cases, those
unable to purchase drugs from their regular distribution channels have
turned to compounding pharmacies.[Footnote 20] While compounding
pharmacies play a vital role in health care by tailoring drugs to
better meet patients' needs (such as removing a dye from a drug to
prevent an allergic reaction) they are not authorized to prepare drugs
that are copies of commercially available products.
* Disruption of the development of new drugs. Ongoing shortages of
drugs have affected clinical trials (studies in humans) that are used
to gauge the safety and effectiveness of a newly developed drug to
that of a drug known to be effective. The inability to obtain adequate
supplies of drugs, such as oncology drugs, has resulted in clinical
trials being suspended indefinitely. Without such trials, new drugs
cannot move forward through the development process.
FDA Oversight of Drugs:
FDA is responsible for overseeing the safety and effectiveness of
drugs. Within FDA, the Center for Drug Evaluation and Research (CDER)
manages these responsibilities. FDA's approval is required before new
drugs and generic drugs--drugs that are copies of approved drugs--can
be marketed for sale in the United States.[Footnote 21] To obtain
FDA's approval for a new drug, sponsors must submit a new drug
application (NDA) containing data on the safety and effectiveness of
the drug as determined through clinical trials and other research for
review by CDER's Office of New Drugs (OND). Sponsors of generic drugs
may obtain FDA approval by submitting an abbreviated new drug
application (ANDA) to the agency for review by CDER's Office of
Generic Drugs (OGD). The ANDA contains data showing, among other
things, that the generic drug is bioequivalent to, or performs in the
same manner as, a drug approved through the NDA process.[Footnote 22]
Once the agency receives an NDA, it is reviewed by one of OND's
medical review divisions, depending on the indication the drug has
been proposed to treat. ANDA applications are reviewed by OGD to
determine bioequivalence to approved drugs. In reviewing each
application, FDA considers whether the proposed product labeling
clearly states the condition and population the product is intended to
treat. If the agency determines that a new drug is safe and effective
for its intended use (that its clinical benefits outweigh its
potential health risks) or that a generic drug is bioequivalent to a
previously approved drug, and that other requirements are met, it will
approve the application. After obtaining FDA's approval, drug
companies that want to change any part of their original application--
such as changes to product manufacturing location or process, type or
source of active ingredients, or the product's labeling--must
generally submit an application supplement to obtain FDA's review and,
if the change has a substantial potential to have an adverse effect on
the product, approval.[Footnote 23]
After approving new and generic drugs for marketing, FDA's
responsibilities continue as it is charged with monitoring the safety,
effectiveness, quality, and promotion of approved drugs, and the
agency may take enforcement actions in response to violations of laws
and regulations. However, FDA may exercise regulatory discretion in
deciding what actions to take or when to take them. For example, as
part of its efforts to ensure the safety of approved drugs, FDA
periodically inspects drug manufacturing establishments to assess
their ongoing compliance with quality standards.[Footnote 24] If FDA
finds manufacturing deficiencies, it may request that the manufacturer
take corrective actions, or it may take enforcement action to require
the manufacturer to take corrective actions. FDA may also take steps
to ensure that manufacturers do not disseminate false or misleading
information about a drug. Drugs whose labeling includes information
not consistent with the labeling approved by FDA are considered
misbranded and may be subject to regulatory action. FDA could seek
civil monetary penalties from manufacturers that have misbranded their
drugs.
FDA Oversight of Drug Shortages:
FDA's response to drug shortages is managed by CDER's Drug Shortage
Program. The agency maintains a website that includes information
about how drug shortages can be reported to the Drug Shortage Program,
and encourages manufacturers and the public to report shortages. Once
the Drug Shortage Program becomes aware of a potential or actual
shortage, agency officials attempt to determine whether the total
supply of the drug and any pharmaceutical equivalents is inadequate to
meet demand--FDA's definition of a shortage.[Footnote 25] To make this
determination, Drug Shortage Program officials contact manufacturers
of the drug to confirm how much inventory remains and how much of the
drug they are currently producing. Drug Shortage Program officials
compile this information and compare it to pharmaceutical industry
sales data, including that which is available from IMS Health, in
order to determine historical demand for the product. If the amount of
the drug--or pharmaceutical equivalents--is insufficient to meet
market demand, the agency considers the drug to be in shortage, and
the Drug Shortage Program takes actions intended to alleviate and
resolve the shortage.
FDA's Drug Shortage Program also collaborates with ASHP to identify
new drug shortages; however, ASHP also tracks shortages that do not
meet FDA's definition of a shortage. Once the Drug Shortage Program
determines that a shortage is in effect, it may coordinate its
response with several CDER offices, including OGD, OND, and the Office
of Compliance. If a drug in shortage is manufactured by a company
involved in a regulatory action, the Office of Compliance may also
work with FDA's Office of Regulatory Affairs and the company to
mitigate and remediate the underlying problem.
Federal Strategic and Workforce Planning:
The use of strategic planning can help federal agencies manage their
programs more effectively by developing strategies to address current
and future management challenges. To be successful, strategic plans
should include clearly established goals and objectives and a
description of how program activities can serve those goals. We have
previously reported on a variety of leading practices for successful
strategic planning.[Footnote 26] One such practice is the development
of a set of results-oriented performance measures, which provide an
important way of helping to evaluate program performance, demonstrate
progress in achieving results, balance competing priorities, and
inform decision making. When possible, such measures should
demonstrate a program's contributions toward the long-term outcomes,
or the results the agency expects a program to achieve. Given FDA's
mission of ensuring the public health, we have previously noted that
the agency's long-term outcomes should be focused on this mission.
[Footnote 27] When long-term outcomes may be influenced by multiple
agency programs and external factors, short-term and intermediate
measures can also demonstrate a program's specific contribution to a
long-term outcome.[Footnote 28]
Another important management tool is workforce planning, which helps
agencies to align their workforce with current and future program
needs and develop long-term strategies for recruiting, training, and
retaining staff.[Footnote 29] Workforce planning assists agencies in
thinking strategically about how to put the right people in the right
jobs at the right time. Although approaches to such planning can vary
by agency, depending on an agency's unique needs and mission,
workforce plans should share certain principles, such as the
identification of skills and competencies to fill critical workforce
gaps and the strategies needed to recruit them.
We have previously reported on the need for FDA to improve its
strategic planning and performance metrics. In 2010, we reported that
FDA was not fully utilizing practices for effective strategic and
workforce planning.[Footnote 30] We found that most of FDA's
established performance measures were not results-oriented as they did
not focus on actual public health outcomes. In addition, we reported
that FDA lacked clear linkages between its resources and goals,
generally did not track workload by strategic goals, and that only
about one-third to one-half of FDA managers used performance
information to a great extent in making management decisions, such as
setting program priorities. We also noted that FDA's internal
coordination was one of the major management challenges facing the
agency. We recommended, and FDA agreed, that the agency issue an up-to-
date strategic workforce plan, make its performance measures more
results-oriented, and more clearly align center and office program
activities to FDA's strategic goals. In January 2009 we added FDA's
oversight of medical products to our High-Risk List because FDA
continued to face multiple challenges that threatened to compromise
its ability to protect the public health. In 2011, in an update to our
High-Risk Series, we noted that although FDA had begun taking steps to
improve its oversight, the agency needs to do more to resolve
concerns, such as by improving resource management and strategic
planning, responding to globalization, and overseeing postmarket
safety.[Footnote 31]
The Number of Drug Shortages Has Grown Substantially Since 2006, and
Many Involved Generic Injectable Drugs:
Our analysis of the trends in drug shortages that were reported from
January 2001 through June 2011 showed that the number of drug
shortages reported has grown substantially since 2006, and many
shortages since 2009 have involved generic injectable drugs.
The Number of Drug Shortages Has Grown Substantially Since 2006:
Since 2006, the number of drug shortages reported each year has grown
substantially. In total, 1,190 drug shortages were reported to ASHP
from January 2001 through June 20, 2011, according to our analysis of
UUDIS data.[Footnote 32] The number of drug shortages reported varied
from year to year, and from 2001 through 2006, generally declined.
However, from 2006 through 2010, the number of drug shortages
increased each year, and grew by more than 200 percent over this
period. A record number of shortages (196) were reported in 2010, and
2011 is on pace to surpass 2010's record, with 146 shortages reported
through June 20, 2011. (See figure 1.)
Figure 1: Number of Drug Shortages Reported January 1, 2001, through
June 20, 2011, by Year:
[Refer to PDF for image: vertical bar graph]
Year: 2001;
Number of drug shortages reported: 103.
Year: 2002;
Number of drug shortages reported: 80.
Year: 2003;
Number of drug shortages reported: 71.
Year: 2004;
Number of drug shortages reported: 54.
Year: 2005;
Number of drug shortages reported: 71.
Year: 2006;
Number of drug shortages reported: 64.
Year: 2007;
Number of drug shortages reported: 114.
Year: 2008;
Number of drug shortages reported: 138.
Year: 2009;
Number of drug shortages reported: 153.
Year: 2010;
Number of drug shortages reported: 196.
Year: 2011;
Number of drug shortages reported: 148 (shortages reported through
June 20).
Source: GAO analysis of University of Utah Drug Information Service
data.
[End of figure]
Over half (64 percent, or 766) of the 1,190 shortages represent drugs
that were in shortage more than once. Specifically, 283 drugs were in
shortage on multiple occasions during this time frame, representing
766 individual shortages. These 283 drugs were each in short supply
between two and eight times during this period, with an average of 2.7
times per drug. Over the entire time period, the 283 drugs were in
short supply for an average of nearly 2 years.
While the duration of the reported shortages varied considerably,
most--74 percent--of the shortages lasted 1 year or less.[Footnote 33]
However, an additional 16 percent, or 178, lasted between 1 and 2
years, and 10 percent (110) lasted more than 2 years. (See figure 2.)
The duration of these shortages varied greatly, ranging from 1 day to
over 7 years.
Figure 2: Distribution of the Duration of Reported Drug Shortages,
January 1, 2001, through June 20, 2011:
[Refer to PDF for image: vertical bar graph]
Up to 1 year: 810;
11-2 years: 178;
2-3 years: 66;
3 or more years: 44.
Source: GAO analysis of University of Utah Drug Information Service
data.
Note: Our analysis on the duration of the shortages includes 1,098 of
the 1,190 total shortages reported from January 1, 2001, through June
20, 2011; we excluded 92 shortages from this analysis because the
University of Utah Drug Information Service listed these shortages as
lasting zero days; the majority of these represented manufacturers'
decisions to discontinue their production of a drug.
[End of figure]
Overall, the average duration of the drug shortages over this period
was 286 days--or over 9 months. The average duration of shortages was
longer for shortages that were active as of June 20, 2011 (360 days,
or nearly 12 months) in comparison to those that were resolved by that
time (266 days, or nearly 9 months). (See table 1.)
Table 1: Summary of the Duration of Drug Shortages, January 1, 2001,
through June 20, 2011, by Shortage Status:
Summary of shortage duration: Resolved shortages;
Total number of shortages: 868;
Average duration (in days): 266;
Median duration (in days): 148.
Summary of shortage duration: Active shortages (as of June 20, 2011);
Total number of shortages: 230;
Average duration (in days): 360;
Median duration (in days): 256.
Summary of shortage duration: All active and resolved shortages;
Total number of shortages: 1098;
Average duration (in days): 286;
Median duration (in days): 159.
Source: GAO analysis of University of Utah Drug Information Service
data.
Note: Our analysis on the duration of the shortages includes 1,098 of
the 1,190 total shortages reported from January 1, 2001, through June
20, 2011; we excluded 92 shortages from this analysis because the
University of Utah Drug Information Service listed these shortages as
lasting zero days; the majority of these represented manufacturers'
decisions to discontinue their production of a drug.
[End of table]
Generic Injectable Drugs Comprised Over Half of Critical Shortages
Since 2009:
Based on our review of the characteristics of a smaller group of
critical drug shortages reported between January 1, 2009, and June 20,
2011, we found that over half involved generic injectable drugs.
Specifically, 53 percent of the 269 drug shortages reported during
this time period involved generic injectable drugs.[Footnote 34] About
39 percent of shortages involved injectable drugs that were available
only in generic form, and about 14 percent involved injectable drugs
available in both brand-name and generic form. An additional 15
percent of shortages involved injectable drugs that were available in
brand-name form only. The remaining portion of shortages--about 32
percent--involved either brand-name or generic drugs that were
administered through other routes. (See figure 3.)
Figure 3: Distribution of 269 Critical Drug Shortages Reported January
1, 2009, through June 20, 2011, by Product Type and Route of
Administration:
[Refer to PDF for image: pie-chart]
Injectable drugs available in generic form: 53%;
Injectable drugs available only in brand-name form: 15%;
Orally-administered drugs available in generic form: 16%;
Orally-administered drugs available only in brand-name form: 4%;
Other drugs[A]: 12%.
Source: GAO analysis of University of Utah Drug Information Service
and Red Book data.
Note: This figure reflects 269, or 54 percent, of the 495 total
shortages reported January 1, 2009, through June 20, 2011. Our
analysis was limited to the shortages the University of Utah Drug
Information Service identified as critical.
[A] Other drugs include those administered via nasal, inhalation,
rectal, topical, ophthalmic, and transdermal methods, as well as those
that are available for administration through multiple routes and one
drug whose route of administration was unavailable from Red Book.
[End of figure]
The share of critical drug shortages involving generic injectable
drugs has increased. Specifically, from 2009 through 2010, the share
of reported shortages involving generic injectable drugs grew from 37
percent to 64 percent. Forty-six critical shortages reported in 2011
through June 20 involved generic injectable drugs; this represents 56
percent of all such shortages.
Generic drugs were more often in shortage than brand-name drugs.
Overall, about three-fourths (76 percent) of the 269 drug shortages
involved drugs that were available in generic form, with nearly half
of all shortages involving drugs that were available only in generic
form. Twenty-four percent of these drug shortages involved only brand-
name drugs. (See table 2.) The share of reported drug shortages
involving generic drugs--including those with a brand-name
counterpart--remained relatively stable from January 1, 2009, through
June 20, 2011.
Table 2: Summary of 269 Critical Drug Shortages Reported January 1,
2009, through June 20, 2011, by Product Type:
Product type: Brand-name only;
Number of shortages: 64;
Percent: 24%.
Product type: Generic only;
Number of shortages: 133;
Percent: 49%.
Product type: Brand-name and generic drugs;
Number of shortages: 72;
Percent: 27%.
Product type: Total;
Number of shortages: 269;
Percent: 100%.
Source: GAO analysis of University of Utah Drug Information Service
and Red Book data.
Note: This table reflects 269, or 54 percent, of the 495 total
shortages reported January 1, 2009, through June 20, 2011. Our
analysis was limited to the shortages the University of Utah Drug
Information Service identified as critical.
[End of table]
Among the 269 critical drug shortages, those administered by injection
were the most commonly in shortage. In total, 68 percent of drug
shortages involved drugs administered by injection. (See table 3.)
Additionally, the share of shortages involving injectable drugs grew
from 51 percent to 77 percent between 2009 and 2010. Fifty-nine
critical shortages reported in 2011 (through June 20) involved
injectable drugs; this represents 72 percent of the shortages.
Table 3: Summary of 269 Critical Drug Shortages Reported January 1,
2009, through June 20, 2011, by Route of Administration:
Route of administration: Injection;
Number of shortages: 182;
Percent: 68.
Route of administration: Oral;
Number of shortages: 56;
Percent: 21%.
Route of administration: Other[A];
Number of shortages: 28;
Percent: 10%.
Route of administration: Multiple routes;
Number of shortages: 3;
Percent: 1%.
Route of administration: Total;
Number of shortages: 269;
Percent: 100%.
Source: GAO analysis of University of Utah Drug Information Service
and Red Book data.
Note: This table reflects 269, or 54 percent, of the 495 total
shortages reported January 1, 2009, through June 20, 2011. Our
analysis was limited to the shortages the University of Utah Drug
Information Service identified as critical.
[A] Other routes of administration included nasal, inhalation, rectal,
topical, ophthalmic, and transdermal, as well as one drug whose route
of administration was unavailable from Red Book.
[End of table]
Certain therapeutic classes were more likely than others to be
affected by a shortage. Specifically, five therapeutic classes--
anesthetic and central nervous system (CNS), anti-infective,
cardiovascular, nutritive, and oncology drugs--represented 68 percent
of critical drug shortages. Anesthetic and CNS drugs were the most
represented therapeutic class, with 23 percent of shortages reported.
(See table 4.)
Table 4: Summary of 269 Critical Drug Shortages Reported January 1,
2009, through June 20, 2011, by Therapeutic Class:
Therapeutic class: Anesthetic and central nervous system drugs;
Number of shortages: 61;
Percent: 23%.
Therapeutic class: Anti-infective drugs;
Number of shortages: 37;
Percent: 14%.
Therapeutic class: Nutritive agents;
Number of shortages: 30;
Percent: 11%.
Therapeutic class: Oncology drugs;
Number of shortages: 28;
Percent: 10%.
Therapeutic class: Cardiovascular drugs;
Number of shortages: 26;
Percent: 10%.
Therapeutic class: Endocrine and metabolic drugs;
Number of shortages: 14;
Percent: 5%.
Therapeutic class: Toxicology antidote drugs;
Number of shortages: 10;
Percent: 4%.
Therapeutic class: Dermatological drugs;
Number of shortages: 9;
Percent: 3%.
Therapeutic class: Musculoskeletal drugs;
Number of shortages: 9;
Percent: 3%.
Therapeutic class: Other[A];
Number of shortages: 41;
Percent: 15%.
Therapeutic class: Multiple therapeutic classes;
Number of shortages: 4;
Percent: 1%.
Therapeutic class: Total[B];
Number of shortages: 269;
Percent: 99%.
Source: GAO analysis of University of Utah Drug Information Service
and Red Book data.
Note: This table reflects 269, or 54 percent, of the 495 total
shortages reported January 1, 2009, through June 20, 2011. Our
analysis was limited to the shortages the University of Utah Drug
Information Service identified as critical.
[A] Includes other therapeutic classes such as gastrointestinal drugs
and ophthalmologic drugs, as well as one drug whose therapeutic class
was unavailable from Red Book.
[B] Percentages do not sum to 100 due to rounding.
[End of table]
Although the numbers are small, shortages of oncology drugs rose
significantly between 2009 and 2010. Specifically, the number of
reported shortages for oncology drugs increased by 600 percent, from 2
shortages in 2009 to 14 shortages in 2010. Additionally, the number of
reported oncology drug shortages in 2011 (12 shortages as of June 20,
2011) is on pace to surpass the total number of such shortages in
2010. Other therapeutic classes saw increases in the number of
shortages reported from 2009 to 2010: endocrine and metabolic drugs (3
to 7, or 133 percent); nutritive agents (5 to 13, or 160 percent); and
toxicology antidote drugs (1 to 4, or 300 percent).
Anesthetic and CNS drugs and anti-infective drugs saw decreases in the
number of shortages reported between 2009 and 2010, at 16 and 25
percent, respectively. However, shortages for these therapeutic
classes reported through June 20, 2011, are on pace to surpass the
total number of such shortages reported in 2010, and remain among the
most commonly reported shortages.
We noted several other characteristics among these drug shortages.
Specifically, 59 percent of drug shortages involved more than one
manufacturer--meaning that most shortages reflected disruptions in the
supply of more than one manufacturer's drugs. Additionally, 35 percent
of these drug shortages involved at least one discontinued product--
such as one strength or package size of a drug that was in short
supply. In such cases, a manufacturer's decision to discontinue a
product may have caused the shortage, or may have occurred during an
ongoing shortage.
Drug Shortages We Reviewed Were Generally Caused by Manufacturing
Problems and Exacerbated by Multiple Difficulties:
Our analysis of the causes of 15 sterile injectable drug shortages
(involving 5 anesthesia drugs, 5 anti-infective drugs, and 5 oncology
drugs) showed that manufacturing problems were the primary cause of
most shortages, and over half were exacerbated by multiple
difficulties after the drug initially went into short supply.
Manufacturing Problems Reportedly Caused Most of the 15 Shortages of
Sterile Injectable Drugs:
Most (12 of the 15) drug shortages we reviewed in detail were
reportedly caused by manufacturing problems, including those that
resulted in manufacturing shutdowns, according to information provided
by FDA and manufacturers. The remaining 3 shortages were reportedly
caused by disruptions in the supply of APIs. (See figure 4.) These
problems were the primary cause of the shortages reviewed--that is,
the first event that triggered the drug shortage.
Figure 4: Summary of Primary Causes of 15 Sterile Injectable Drug
Shortages That Occurred Between January 2009 and June 2011:
[Refer to PDF for image: pie-chart and sub-chart]
Primary causes of shortages:
Manufacturing problems: 12;
Disruption in the supply of active pharmaceutical ingredients: 3.
Types of manufacturing problems:
Temporary manufacturing shutdown to upgrade an entire facility: 6;
Temporary manufacturing suspension of a particular drug to investigate
or resolve a manufacturing problem: 4;
Unspecified manufacturing delays: 2.
Source: GAO analysis of information provided by FDA and manufacturers.
[End of figure]
Of the 12 shortages caused by manufacturing problems, 6 resulted from
manufacturers' temporary shutdowns of entire facilities so they could
be upgraded. Four of these six shortages were caused by one
manufacturer's shutdown of a single facility. Representatives from
this manufacturer told us that it shut down the facility in order to
improve its manufacturing capabilities. The manufacturer had
anticipated that the upgrade would take 3 months, but it took 1 year
to complete. Prior to the shortage, the manufacturer built up its
inventory to ensure that it could meet the market's demand for its
products during the expected 3-month shutdown. However, because the
manufacturer had not planned for an extended shutdown, 4 of the 15
drug shortages we reviewed, as well as other sterile injectable drugs
produced at that facility, went into short supply.
Another four shortages we reviewed were caused when manufacturers
temporarily suspended production of a particular drug in order to
investigate or resolve a specific manufacturing problem--for example,
a quality problem. The remaining two shortages were caused by
unspecified manufacturing delays.
Officials from FDA and manufacturers explained that sterile injectable
drugs are complex to make, and as such, can be prone to manufacturing
and quality problems. These products require a sterile environment,
which is difficult to maintain. FDA officials told us that the most
common manufacturing problems experienced for sterile injectable drugs
are lack of assurance of sterility and particulate matter included in
the drug. According to FDA officials, sterile injectable drugs can
take weeks to produce; in comparison, oral tablets may only take up to
a few days to produce. The complexity and duration of the
manufacturing process for sterile injectable drugs makes these drugs
more susceptible to manufacturing problems. In addition, according to
FDA, such drugs are being made by a decreasing number of aging
facilities, which may contribute to the recent increase in
manufacturing problems.
Certain types of sterile injectable drugs, such as anti-infective and
oncology drugs, can be particularly challenging to manufacture.
Officials from FDA and other organizations we interviewed explained
that manufacturers of sterile injectable anti-infective and oncology
drugs face unique challenges because of the nature of the drugs'
ingredients. Specifically, some anti-infective drugs, such as
penicillin, are highly sensitizing and can trigger serious allergic
reactions at very low levels. As a result, FDA requires manufacturers
to produce penicillin in isolation from other drugs.[Footnote 35] In
addition, some oncology drugs are toxic and can present serious risks
to people who come into contact with these compounds, even at low
concentrations. As a result, FDA suggests that manufacturers of
oncology drugs consider using dedicated production lines in order to
ensure that other products are not contaminated. According to FDA
officials, the special containment controls necessary for some
oncology and anti-infective drugs can limit manufacturers' transfer of
production of these drugs to other lines. As a result, manufacturers
may have increased difficulty keeping up with demand for such products
when they are in short supply.
Most of the drugs involved in the shortages we reviewed have been
available in generic form for over 15 years. When asked how the prices
and profits for their generic sterile injectable drugs have affected
manufacturers' interest in maintaining, upgrading, or increasing
redundancy within their manufacturing lines, or in continuing to
manufacture these drugs, three of the four manufacturers we contacted
stated that such factors had no effect on decisions they make for
their current product portfolio. These manufacturers indicated that
they are committed to the sterile injectable drug market or to
appropriately supporting the manufacture of their current portfolio of
drugs. However, one of these three manufacturers told us that such
factors may affect future decisions it makes about the products it
manufactures. In contrast, the fourth manufacturer told us that it
carefully weighs factors, including market demand and product price
erosion for generic drugs, when making capital investment decisions.
This manufacturer added that in its opinion, lower profits available
for the manufacture of generic drugs have led to much lower levels of
redundancy in manufacturing generic drugs than for brand-name drugs.
Despite this, officials from three of the four manufacturers we
contacted told us that they continue to produce drugs that garner low
or no profits. Rather than assessing the profitability of any single
drug product, they instead make business decisions based of their
overall portfolio of drugs or concerns for patients.
Three of the 15 shortages of sterile injectable drugs we reviewed in
detail were caused by disruptions in the supply of APIs. For 2 of
these shortages, manufacturers were not receiving their normal
shipments of API because of problems related to the manufacturing of
these ingredients. For 1 shortage, the manufacturer's supplier of API
discontinued its production of the ingredient, which led to the
shortage.
Over Half of the 15 Shortages Were Subsequently Exacerbated by
Multiple Difficulties:
In addition to the initial problems that caused the shortages, over
half of the shortages we reviewed (8 of 15) were subsequently
exacerbated by multiple other difficulties that arose after the
shortages began. These 8 shortages were each affected by an average of
four distinct difficulties that occurred in addition to the primary
cause of the shortage and generally affected multiple manufacturers.
Four of these shortages were exacerbated by five or more difficulties-
-including 1 shortage that was exacerbated by seven distinct
difficulties. In addition to the 8 shortages that were exacerbated by
multiple issues, 4 were exacerbated by one issue after the drug
initially went into short supply. The factors that impacted drug
shortages did not vary substantially by the drugs' therapeutic class.
The two most common difficulties that exacerbated shortages after the
drugs went into short supply were other manufacturers' inability to
keep up with an increased demand for their products once a
competitor's drug went into short supply, and manufacturing problems,
including those that involved manufacturing shutdowns. Each of these
difficulties affected 9 shortages. The drugs involved in the 15
shortages we reviewed were produced by an average of three
manufacturers at the time the drug went into short supply. According
to officials from FDA and manufacturers, when only a few make a drug
and one manufacturer's drug is in short supply, it can be difficult
for the others to substantially increase production of a drug to
ensure that demand for a drug is met--even in the absence of any other
problems.
Some of the 15 shortages we reviewed were subsequently exacerbated by
other difficulties in addition to their primary causes. For example, 5
shortages were exacerbated by manufacturers' decisions to discontinue
a drug. In addition, 3 drug shortages were exacerbated by
manufacturers' decisions to recall products for product quality
reasons, including 1 shortage that was exacerbated by two drug
recalls. Finally, 2 shortages were exacerbated by disruptions in the
supply of API, and 1 was exacerbated by a delay related to the
importation of a finished drug product. (See table 5.)
Table 5: Summary of Difficulties That Subsequently Exacerbated 15
Sterile Injectable Drug Shortages That Occurred Between January 2009
and June 2011:
Difficulties affecting drug supply: Manufacturers' inability to keep
up with demand;
Number of shortages affected: 9.
Difficulties affecting drug supply: Manufacturing problems[A];
Number of shortages affected: 9.
Difficulties affecting drug supply: Manufacturing problems[A];
Temporary manufacturing shutdown in order to upgrade an entire
facility;
Number of shortages affected: 2.
Difficulties affecting drug supply: Manufacturing problems[A];
Temporary manufacturing suspension of a particular drug in order to
investigate or resolve a manufacturing problem;
Number of shortages affected: 5.
Difficulties affecting drug supply: Manufacturing problems[A];
Temporary manufacturing shutdown for unspecified reasons;
Number of shortages affected: 1.
Difficulties affecting drug supply: Manufacturing problems[A];
Manufacturing delays;
Number of shortages affected: 3.
Difficulties affecting drug supply: Manufacturing problems[A]; Other
manufacturing problems;
Number of shortages affected: 1.
Difficulties affecting drug supply: Product discontinuations;
Number of shortages affected: 5.
Difficulties affecting drug supply: Disruption in the supply of active
pharmaceutical ingredients;
Number of shortages affected: 2.
Difficulties affecting drug supply: Delays associated with the
importation of finished drug products;
Number of shortages affected: 1.
Source: GAO analysis of information provided by FDA and manufacturers.
Note: The number of shortages affected by these difficulties is
greater than the number of shortages reviewed because most of the
shortages we reviewed were affected by multiple difficulties, such as
multiple types of manufacturing problems.
[A] As a result of manufacturing problems, three drug shortages were
affected by recalls and one of these shortages experienced two product
recalls.
[End of table]
During these shortages, multiple manufacturers sometimes experienced
the same exacerbating issues, once a shortage was already ongoing. For
example, 9 of the 15 shortages we reviewed were extended as a result
of manufacturing problems that occurred in addition to the shortages'
primary causes, as displayed in table 5 above. During 2 of these
shortages, three manufacturers of the drugs in shortage each
experienced manufacturing problems; during another shortage, two
manufacturers each experienced such problems, and during the remaining
6 shortages, one manufacturer experienced manufacturing problems.
Officials from one manufacturer described recent shortage situations
as a perfect storm of several manufacturers coincidentally
experiencing manufacturing problems all at the same time.
Three shortages we reviewed were not affected by issues beyond the
primary cause of the shortage. One of these shortages involved a drug
that was produced by only one manufacturer at the time of the
shortage. The other two shortages were not exacerbated by other issues
because, according to FDA, other manufacturers were able to produce
enough of the drug to meet the market's demand.
Actions Taken by FDA to Respond to Drug Shortages Are Intended to
Resolve Shortages' Underlying Causes and Enhance Product Availability:
FDA responds to drug shortages by taking various actions to address
the shortages' underlying causes and enhance product availability. Our
analysis of FDA's response to 15 shortages of sterile injectable drugs
showed that FDA took a variety of actions to respond to each shortage.
In addition, FDA has increasingly prevented drug shortages from
occurring. FDA primarily communicates information about drug shortages
and product availability to the public through its website.
FDA's Goal Is to Resolve the Underlying Causes of Shortages:
FDA attempts to address the underlying cause of shortages as well as
to provide ways to enhance the drug's availability until the
underlying cause of the shortage has been addressed and the shortage
is resolved, according to FDA officials we interviewed. FDA officials
explained that they respond to all of the shortages the agency becomes
aware of, and they determine how to address each shortage based on its
cause and the public health risk associated with the shortage. Along
with this determination, FDA officials told us that the agency places
the highest priority on responding to shortages of those drugs that it
considers medically necessary--that is, those that have the greatest
potential to affect public health.[Footnote 36] FDA defines a
medically necessary drug as any drug that is used to treat or prevent
a serious disease or medical condition for which there is no other
adequately available drug that is judged by medical staff to be an
appropriate substitute.[Footnote 37] FDA's goal in identifying such
drugs is to assist in the prioritization of their response to drug
shortages. As such, FDA's determination of whether a drug is medically
necessary may differ from a health care provider's assessment that a
certain drug is needed to treat a particular patient. FDA officials
told us that they sometimes consult with health professional
organizations such as ASHP when making a determination regarding the
medical necessity of a particular drug. During shortages, FDA
officials told us that if a drug is determined to be medically
necessary, they will inform the manufacturer of their decision.
Appendix I summarizes the criteria FDA uses to determine whether a
drug is medically necessary.
FDA may take a variety of actions to respond to the shortages of
medically necessary and non-medically necessary drugs by providing
assistance directly to the manufacturer. If a manufacturer is
experiencing technical problems with its manufacturing processes, FDA
may be able to assist in the resolution of those problems--for
example, by providing advice on how to address quality issues and
ensure compliance with current good manufacturing practice
regulations. If the manufacturer is facing difficulties obtaining raw
materials, FDA may be able to assist in identifying an alternative
supplier. Similarly, if a manufacturer is unable to obtain APIs or a
finished drug as a result of importation delays, FDA may be able to
coordinate with other entities, such as other federal agencies, to
enable these materials to be imported more quickly.
During a shortage, FDA may encourage manufacturers to increase
production of the drug or to seek approval to begin production of a
drug in short supply. If more than one manufacturer produces the drug
that is in short supply, FDA may contact the other manufacturers to
alert them to the potential of increased demand and may encourage them
to increase their production of the drug. During shortages involving
generic drugs, FDA may also encourage other manufacturers to submit
ANDAs for review, so that additional manufacturers can gain FDA
approval to produce the drug that is in short supply.
FDA may also expedite its review of ANDAs, ANDA supplements, and NDA
supplements during a shortage, but this is largely dependent on the
manufacturers' request for an expedited review. Some shortages may be
resolved with changes to a manufacturing process or site, or the use
of an alternative supplier for an API. FDA reviews manufacturers'
requests for such changes, as documented in an application supplement,
and any changes that have substantial potential to have an adverse
effect on the product must be approved prior to their implementation.
To assist in resolving a shortage, FDA may expedite its review of
these supplements, or may expedite its review of ANDAs, which can
substantially decrease the agency's review time.[Footnote 38] FDA
officials told us that an expedited review involves the same amount of
analysis as a review that is not expedited, but can take significantly
less time since the agency prioritizes its review of such
applications. For example, FDA officials noted that certain expedited
ANDA supplements have been approved in as quickly as a few days to a
week, in contrast to the year or more it may take for such supplements
to be reviewed under the typical process. FDA's review of NDA
supplements in 2009 took the agency an average of 5 months, while
those that were expedited took an average of 2.5 months.[Footnote 39]
FDA has encouraged manufacturers to note their request for an
expedited review due to a shortage in their cover letter to an
application supplement or ANDA, or to inform FDA officials working in
the Drug Shortage Program, OND, or OGD directly.
FDA may also apply its regulatory discretion to enhance drug
availability during shortages of medically necessary drugs.[Footnote
40] When considering whether to apply its regulatory discretion, the
agency weighs the risks and benefits of taking such an approach. For
example, FDA may exercise its regulatory discretion for manufacturers
to continue marketing a medically necessary drug despite labeling or
quality issues that would typically result in regulatory action. While
FDA considers a drug with labeling errors to be misbranded, to
alleviate or resolve a shortage of a medically necessary drug, agency
officials told us that FDA may exercise its regulatory discretion with
regard to a manufacturer's continued marketing of a drug with labeling
errors. In this scenario, the manufacturer would issue an FDA-reviewed
letter to health care professionals informing them of the error, or
provide the corrected label text. FDA may also apply its regulatory
discretion with regard to manufacturers' continued marketing of
medically necessary drugs that have quality problems, if the
manufacturer can develop a method to resolve the problem prior to the
drug's administration. For example, if a manufacturer finds
particulate in a drug and determines that a filter can be used to
remove the particulate prior to administration of the drug, at FDA's
discretion, the manufacturer may continue to market the drug with the
filter. In such cases, FDA would review evidence of the filter's
effectiveness provided by the manufacturer, to ensure that it removes
the particulate from the drug.
If FDA is unable to resolve or alleviate a shortage of a medically
necessary drug within the United States, the agency may use its
regulatory discretion with regard to the importation into the United
States of "unapproved drugs." These drugs are approved for use in
foreign countries, but not the United States. For example, FDA
officials told us that from January 2011 through September 2011, at
the agency's discretion, manufacturers imported seven unapproved drugs
into the United States to address drug shortages. Four of these
importations were ongoing as of October 3, 2011. FDA officials we
interviewed explained that they only consider using this option for
severe shortages of medically necessary drugs. To explore whether the
importation of drugs not approved in the United States is an option
for agency discretion during a shortage, agency officials told us that
FDA collaborates with foreign regulatory agencies to identify whether
a similar drug is manufactured in a country that requires adherence to
manufacturing practice standards that are similar to those required by
FDA. Once any such manufacturers are identified, FDA asks the firm
whether they would be willing to provide the drug for the U.S. market.
When possible, FDA selects a firm that has a subsidiary in the United
States and an existing distribution network in order to expedite the
process and the agency's access to information about the foreign
manufacturing facility and drug. To help ensure the quality of the
drug, FDA officials told us that they examine information about the
manufacturer, its manufacturing facility, the chemical formulation of
the drug, and information about the manufacturer's quality control
processes. FDA also reviews the firm's compliance history and
inspection reports that foreign regulatory agencies make available.
Agency officials told us that, depending on the amount and currency of
available information about the manufacturing facility, they may
conduct an inspection prior to the importation of the unapproved drug
into the United States. After a manufacturer has been identified and
FDA has completed its quality review, FDA works with the company to
reach an agreement on the conditions of the agency's enforcement
discretion and monitors the supply and distribution of the drug that
comes into the United States. FDA also encourages manufacturers to
communicate with health care professionals and the public about
potential differences between the imported drug and the drug in
shortage through the use of letters to health care professionals.
These letters detail any differences in chemical composition,
strength, or formulation between the imported drug and the drug in
short supply. FDA officials told us that, at their discretion,
importation of such drugs may continue until the manufacturers of the
FDA-approved drug are able to meet demand.
FDA considers a shortage to be resolved when the supply of the drug
meets demand, which FDA calculates using market data that it obtains
from IMS Health. FDA officials told us that they continue to monitor
recently resolved shortages until any ongoing issues that could affect
the supply of the drug are resolved.
FDA Responded to Selected Shortages with a Variety of Actions:
Our review of FDA's response to 15 shortages of sterile injectable
drugs showed that FDA typically used two or more types of actions to
respond to each shortage, and for 8 shortages, the agency responded
with four or more types of actions. At the time of these shortages,
FDA determined that all 15 drugs involved with shortages we reviewed
in detail were medically necessary. To respond to these shortages, FDA
most frequently offered assistance to manufacturers to prevent,
alleviate, or resolve the shortage, or notified other manufacturers to
expect increased demand or encouraged other manufacturers to increase
production, as shown in table 6. (See appendix II for information on
FDA's response to each of the 15 shortages.)
Table 6: Summary of Actions Taken by FDA in Response to 15 Shortages
of Sterile Injectable Drugs That Occurred Between January 2009 and
June 2011:
Types of actions taken by FDA: FDA offered assistance to manufacturers
to prevent, alleviate, or resolve the shortage;
Number of shortages: 15.
Types of actions taken by FDA: FDA notified other manufacturers to
expect increased demand or encouraged other manufacturers to increase
production;
Number of shortages: 13.
Types of actions taken by FDA: FDA provided assistance to address
manufacturing problems related to drug quality issues;
Number of shortages: 8.
Types of actions taken by FDA: FDA searched for a firm willing and
able to import a version of the drug in shortage not approved in the
United States;
Number of shortages: 7.
Types of actions taken by FDA: At FDA's discretion, a manufacturer
imported a version of the drug in shortage not approved in the United
States;
Number of shortages: 1.
Types of actions taken by FDA: FDA expedited its review of an
application supplement or abbreviated new drug application;
Number of shortages: 5.
Types of actions taken by FDA: At FDA's discretion, a manufacturer
continued to market a drug despite labeling or quality issues;
Number of shortages: 5.
Types of actions taken by FDA: FDA provided assistance to address
importation delays for active pharmaceutical ingredients or finished
products;
Number of shortages: 5.
Source: GAO analysis of information provided by FDA.
Note: The total number of types of actions taken by FDA is greater
than the number of shortages reviewed because FDA used more than one
action to respond to most of the shortages we reviewed.
[End of table]
While FDA responded to all of the 15 shortages of sterile injectable
drugs we reviewed, agency officials told us that 3 of these supply
disruptions did not meet the agency's criteria for a shortage.
[Footnote 41] Specifically, FDA officials told us that while it was
aware of disruptions in the supply of these three drugs, the overall
market supply of each drug was able to meet demand, based on the
agency's knowledge of manufacturers' production. Even though FDA did
not recognize these 3 cases as drug shortages, agency officials
nonetheless notified other manufacturers to expect increased demand
for their products or encouraged them to increase production, and also
offered assistance to the affected manufacturers.
FDA Has Increasingly Prevented Potential Drug Shortages from Occurring:
FDA has increasingly prevented potential drug shortages from occurring
when it has been informed of the potential for a shortage in advance.
According to our analysis of information provided by FDA, the agency
prevented 50 potential drug shortages during the first 6 months of
2011--about 1.5 times the number of potential drug shortages (35)
prevented during all of 2010.[Footnote 42] FDA officials partially
attributed the increase in potential shortages prevented to
manufacturers' willingness to report information that could impact the
supply of their drugs in advance of a shortage. The recent increase in
the number of shortages presented additional opportunities for
manufacturers to report potential supply disruptions to the agency.
According to our analysis of information provided by FDA, during the
first half of 2011, the agency was able to prevent about 90 percent of
potential shortages that it learned about in advance.
To prevent these potential shortages, FDA took some of the same types
of actions it uses to alleviate and resolve shortages. During 2010 and
the first half of 2011, FDA most frequently prevented potential drug
shortages by expediting its review of application supplements. FDA
also took a variety of other actions to prevent drug shortages during
this period. (See table 7.)
Table 7: Actions Taken by FDA to Prevent Potential Drug Shortages,
2010 and 2011, through June:
Action taken by FDA: FDA expedited review of application supplements;
Number of actions taken to prevent potential shortages:
2010: 12;
2011[A]: 37.
Action taken by FDA: At FDA's discretion, a manufacturer continued to
market a drug despite labeling or quality issues;
Number of actions taken to prevent potential shortages:
2010: 2;
2011[A]: 9.
Action taken by FDA: FDA helped to ensure timely importation of an
active pharmaceutical ingredient or finished products;
Number of actions taken to prevent potential shortages:
2010: 8;
2011[A]: 2.
Action taken by FDA: FDA either notified firms that they would
experience increased demand or encouraged manufacturers to increase
production;
Number of actions taken to prevent potential shortages:
2010: 9;
2011[A]: 1.
Action taken by FDA: FDA provided assistance to address manufacturing
problems;
Number of actions taken to prevent potential shortages:
2010: 6;
2011[A]: 8.
Action taken by FDA: At FDA's discretion, a manufacturer imported a
version of the drug in shortage not approved in the United States;
Number of actions taken to prevent potential shortages:
2010: 0;
2011[A]: 1.
Action taken by FDA: Other[B];
Number of actions taken to prevent potential shortages:
2010: 1;
2011[A]: 2.
Source: GAO analysis of information provided by FDA.
Note: The total number of actions taken by FDA exceeds the number of
shortages prevented because in some instances, FDA took multiple
actions to prevent shortages.
[A] Data presented for 2011 reflect potential shortages prevented
through June 2011.
[B] Other actions included FDA applying its regulatory discretion with
regard to a manufacturer continuing its production of a drug while
using laboratory testing equipment that the agency had not yet
reviewed.
[End of table]
FDA Communicates Information about Shortages to the Public via Its
Website:
FDA's primary means of communicating information to the public about
drug shortages is its website, which lists both current and resolved
shortages.[Footnote 43] FDA officials told us that they post
information on their website about shortages of medically necessary
drugs, as well as some shortages of non-medically necessary drugs for
which it has received multiple requests for information. However, FDA
may not post any information about shortages if the agency anticipates
that the shortage will be brief in duration. FDA may not immediately
post information about current shortages if the agency is concerned
that such information could make the shortage worse--for example, by
inducing hoarding. Once FDA decides to post information about a
shortage, it lists the manufacturers of the drug as well as a broad
explanation of the cause for the shortage--for example, "manufacturing
issues." FDA may post more detailed information about the cause and
expected duration of the shortage, as well as information about other
versions of the drug that are available, if manufacturers provide them
with text to post on its website, or if the manufacturer makes such
information publicly available.
Once the shortage is resolved--that is, once the supply of the drug is
sufficient to meet the market's demand for it--FDA officials told us
that they may move information about the shortage from its current
shortages web page to its resolved shortages web page. However, FDA
officials told us that they may keep listings of resolved shortages on
its current shortages web page to inform the public about the
availability of the product. In addition, they may keep a shortage
listed as current until they are confident that any underlying causes
of the shortage are addressed. FDA officials told us that they post
information about resolved shortages for 6 months before removing such
information from their website.
FDA Is Constrained in Its Ability to Protect Public Health from Drug
Shortages:
FDA is constrained in its ability to protect the public health from
drug shortages due to its lack of authority to require manufacturers
to take certain actions. In addition, management challenges, such as a
lack of systematic data and performance measures, weaken the agency's
response to drug shortages and inhibit its ability to protect public
health.
FDA Lacks Authority to Require Manufacturers to Report Potential and
Actual Shortages:
FDA is constrained by its lack of authority to require manufacturers
to provide the agency and the public with information about shortages,
or require that manufacturers take certain actions to prevent,
alleviate, or resolve shortages. FDA's sole authority related to
manufacturers' reporting of drug shortages pertains to the
discontinuation of approved drugs that are life-supporting, life-
sustaining, or for use in the prevention of a debilitating disease or
condition, when such drugs are produced by one manufacturer.[Footnote
44] In such instances, companies are required to provide FDA with at
least 6 months notice of discontinuations.[Footnote 45] However, such
discontinuations have not been the primary cause of most recent drug
shortages. As a result of the constraints on its authority, the
agency's approach to managing drug shortages is predominately
reactive, which limits its ability to prevent, alleviate, and resolve
shortages to protect the public health.
FDA does not have the authority to require manufacturers to report
actual or potential shortages--including information about their
causes and expected duration--to the agency or the public. FDA has
encouraged manufacturers to report potential supply disruptions to the
agency. While our draft report was at HHS for comment, the President
directed FDA to use all appropriate administrative tools to require
drug manufacturers to provide adequate advance notice of situations
that could lead to drug shortages, to the extent permitted by law.
[Footnote 46] In addition, on the same day, FDA sent a letter to all
drug manufacturers urging them to report potential supply disruptions
to the agency. According to FDA officials, while the agency could have
been notified in advance of most shortages, less than half of all
shortages are reported to the agency by manufacturers. Instead, FDA is
most often notified by ASHP, or health care providers or consumers
when they are unable to purchase a drug--a point at which the shortage
is already impacting public health. As a result, FDA's response to
shortages may be delayed.
Without information on current or potential shortages, other
manufacturers' ability to increase production of the drug may also be
compromised. For example, one manufacturer told us that FDA did not
notify it soon enough to enable it to increase production to alleviate
or resolve two of the seven shortages that it was involved in and that
were included in our review. In both instances, by the time FDA
informed the manufacturer of the shortage, demand for its products was
already at levels the firm could not support.
Officials from several manufacturers told us that they would like
other manufacturers to openly share information with FDA about
shortages of their drugs because doing so can speed FDA's response,
and can enhance other manufacturers' ability to increase production of
the drug in short supply. These officials told us that they support
efforts to improve communication between FDA and industry through
early notification of potential drug shortages. However, some of these
officials also noted that a requirement to report potential drug
shortages within a specific time frame would be difficult for
manufacturers to observe. They explained that drug shortages can be
unpredictable and are often the unexpected result of several factors
or causes. As a result, they were concerned that manufacturers may not
foresee the impending shortage soon enough to be able to comply with a
lengthy advance notification requirement.
FDA officials also told us that manufacturers sometimes do not provide
the agency with information about the causes and expected duration of
shortages as soon as it is available. As a result, the information
posted on FDA's website does not always reflect current information.
FDA officials told us that they cannot communicate detailed
information about the causes or expected duration of a shortage unless
the affected manufacturers provide text for the agency to post on its
website. FDA officials explained that such information is generally
considered confidential commercial information, which cannot be
disclosed by FDA without the manufacturer's consent. Officials at
several health care professional associations we interviewed noted
that information on the cause and expected duration of a shortage is
important for clinicians to understand so that they can determine the
best method to treat their patients during a shortage.
FDA does not have the authority to require that manufacturers take
certain actions to prevent, alleviate, or resolve shortages, such as
by continuing or increasing their production of a drug, or by taking
actions to prevent or resolve shortages. FDA does not control the
distribution of drugs and also cannot compel manufacturers or
distributors to take actions to prevent hoarding or diversion of drugs
to the gray market. FDA's ability to respond to a drug shortage may be
limited by manufacturers' business decisions, such as a manufacturer
choosing to discontinue production of a drug already in shortage.
While FDA can encourage a manufacturer not to discontinue its
production of a drug, it cannot require the company to continue
production. Also, while it may be in manufacturers' interest to
increase their production of a drug in short supply, FDA cannot compel
a manufacturer to increase its production of a drug. In addition, FDA
cannot compel manufacturers to take steps to resolve shortages, such
as by accepting the agency's offers of assistance. Based on our review
of FDA's response to 15 shortages, we found that manufacturers do not
always accept FDA's offer of assistance. FDA officials also told us
that they encounter challenges finding manufacturers that are willing
to import drugs that are not approved in the United States in order to
alleviate a shortage. Agency officials told us that some manufacturers
had expressed hesitancy in working with FDA to alleviate a shortage in
this manner because it would require a substantial financial
investment accompanied with a time-limited benefit. In our review of
FDA's response to 15 shortages, we found that the agency tried to find
firms that were willing to import drugs that were not approved in the
United States during 7 shortages, but was only able to find a firm to
import a product in order to help alleviate 1 shortage.
Management Challenges Further Constrain FDA's Ability to Respond to
Drug Shortages:
FDA's ability to respond to drug shortages is also constrained by its
lack of systematic data, limited resources, and an absence of
performance measures and priorities. Although FDA obtains information
about drug shortages, the agency does not maintain data related to
these shortages, such as their causes and the agency's response.
Without such data, FDA is unable to systematically monitor trends and
identify actions it could take to address the fundamental or
contributing causes of drug shortages. Drug Shortage Program staff
currently track drug shortages in individual electronic files, not in
a database. To summarize information on drug shortages for other FDA
offices, the Drug Shortage Program prepares e-mail status reports,
which do not present information in a consistent format and are not
conducive to easy retrieval of information or data analysis. In
addition, officials from FDA's Drug Shortage Program, OND, OGD, Office
of Compliance, and ORA told us that they routinely share information
about drug shortages via e-mails, phone calls, or meetings--not in any
systematic format or system. FDA's information does not lend itself to
analysis--it is not easily retrievable, routinely recorded, or
sufficiently reliable. As a result of FDA's lack of systematic data,
the agency was unable to provide us with information necessary to
analyze trends in drug shortages and we therefore obtained these data
from UUDIS.[Footnote 47]
Without a systematic method to store, track, and share data on drug
shortages, the agency cannot ensure that it responds to potential and
current shortages in a timely and coordinated manner. FDA has faced a
growing workload in recent years associated with the increase in the
number of drug shortages reported, but Drug Shortage Program staff
lack a system to manage information to ensure that they are responding
to shortages in a timely manner. The Drug Shortage Program's work
requires staff to maintain a large volume of complex information on
drug shortages, communicate regularly with other agency officials in
other parts of the agency, as well as manufacturers, and monitor
significant shortage situations until they are resolved.[Footnote 48]
Other CDER offices that coordinate with the Drug Shortage Program may
be unaware of information about current or potential shortages and
therefore miss opportunities to respond to shortages--for example, by
neglecting to recognize that supplements submitted for review could
help to alleviate a shortage. While FDA officials told us they review
applications and supplements in the queue to determine whether any
should be expedited in order to alleviate a shortage, representatives
from organizations we interviewed noted concerns about the agency's
ability to review ANDA supplements in a timely manner to prevent,
alleviate, or resolve shortages. Specifically, some representatives
told us that they were aware of instances where manufacturers had
submitted ANDA supplements, which, if approved, could have helped to
alleviate or resolve a shortage.[Footnote 49] According to these
representatives, FDA's review of these supplements can take several
years. In addition, representatives noted that in at least one case,
FDA's review was not expedited until months after the supplement was
received.
FDA officials have acknowledged that a database is needed to store
current and historic data on drug shortages, and in response to this
need, they recently developed, and are in the process of implementing,
an electronic spreadsheet to gather such data. Agency officials told
us that they intend to use this spreadsheet to monitor shortages and
conduct descriptive analyses of shortages in a more standardized
format. In addition, they plan to use this spreadsheet to generate
data to use for annual reporting. We reviewed an early draft of FDA's
spreadsheet and identified several weaknesses. For example, while the
spreadsheet will enhance the agency's ability to more rapidly obtain
and analyze data on drug shortages, it was not intended to--nor will
it provide--a method for FDA to systematically manage information
about drug shortages on a daily basis or provide a means to share
information about drug shortages with other FDA offices. FDA's newly
developed spreadsheet will not enable the agency to improve the
management of its workload, such as its ability to organize the large
volume of information about drug shortages that it receives in a
systematic manner, safeguard institutional knowledge about past
shortages, or help Drug Shortage Program officials share information
with other FDA offices. In addition, because the spreadsheet requires
additional resources for data entry, it will add to the workload of
the Drug Shortage Program--instead of alleviating it. The spreadsheet
is also incomplete and does not allow the agency to track a variety of
datapoints. For example, the spreadsheet does not have a mechanism for
the agency to group together shortages of multiple versions of the
same drug; without this capability, it will be difficult for FDA to
track the number of similar products affected by a shortage.
The spreadsheet also does not include space for FDA to track the NDCs
associated with each drug shortage. Such data are necessary in order
to fully analyze the characteristics of drugs that have been in short
supply. In addition, because FDA's current spreadsheet only includes
space to note one action FDA took to respond to each shortage, it will
not be able to provide the agency with systematic data on multiple
actions the agency takes in response to a shortage. For example, for
shortages involving drugs produced by multiple manufacturers, the
spreadsheet will not be able to systematically capture multiple types
of actions FDA takes to address each shortage.
FDA has consistently staffed its Drug Shortage Program--which is
responsible for the coordination of all of the agency's activities
related to the prevention and mitigation of drug shortages--with a
small number of employees. Despite a dramatic increase in the number
of drug shortages reported in recent years, the number of staff
working in the Drug Shortage Program remained constant at three full-
time employees from 2009 until February 2011, when FDA hired a fourth
staff person for the Drug Shortage Program. As of October 2011, FDA
had hired a fifth staff person, but was unable to provide a time frame
for when that person would start work.[Footnote 50] Because FDA has
lacked detailed data on drug shortages, it may not have been able to
develop reliable estimates of the current and future resource needs of
the Drug Shortage Program, a topic on which we have previously
reported.[Footnote 51] However, representatives from many of the
organizations we interviewed told us that they are concerned that the
agency does not have adequate staffing to effectively respond to drug
shortages.
FDA also does not have a set of results-oriented performance metrics
and strategic priorities related to drug shortages. As a result, FDA
may be unable to effectively evaluate its work and improve its ability
to protect the public health. FDA has not developed a set of results-
oriented performance metrics to measure the success of the agency's
response to drug shortages in either the long term or the short term.
FDA recently began tracking information on one results-oriented
performance metric--the number of drug shortages prevented in a year.
However, FDA lacks other measures that could be used to measure the
results of its work--such as the effectiveness of the actions the
agency takes to respond to shortages. Without such metrics, FDA may be
unable to evaluate how it could most effectively improve the program's
ability to respond to drug shortages and protect the public health.
Furthermore, while FDA has recognized the significant public health
consequences that can result from drug shortages, the agency has not
identified drug shortages as an area of strategic importance for the
agency.[Footnote 52] As a result, the agency may be unable to
coordinate an agencywide response to drug shortages, and make
decisions on the best ways that it can employ its resources to fulfill
its mission to protect the public health.
Conclusions:
The number of drug shortages has substantially increased in recent
years--including those for life-saving medications such as oncology
drugs, which has jeopardized the public health. Health care providers
and patients have struggled with the consequences of these shortages
and have raised concerns about what the federal government is doing to
prevent and resolve these shortages.
FDA may not always be able to prevent shortages from occurring, in
part because it does not have control over private companies' business
decisions, for example, regarding whether to continue making a drug.
Further, the agency's response to drug shortages is constrained by its
lack of authority to require manufacturers to report potential or
current shortages to the agency. FDA has demonstrated that when it
learns of shortages in advance, it can prevent the majority of such
shortages from occurring. However, it does not currently have the
authority to require manufacturers to provide it with information
about potential or current shortages, and therefore it can only
prevent the shortages that it becomes aware of through voluntary
reporting. As a result, FDA's response to shortages is most frequently
reactive. Also, information communicated to health care providers and
the public about shortages may remain incomplete, because FDA cannot
disclose detailed information to the public without manufacturers'
consent.
We have been critical of FDA in the past for not paying sufficient
attention to strategic and workforce planning and reliably estimating
needed resources. Our prior reports have also expressed concern that
the agency has not established result-oriented performance metrics,
that agency managers often do not use existing performance measures to
set program priorities, and that coordination between internal FDA
offices is a significant management challenge. These concerns are
echoed in the agency's current approach to managing its Drug Shortage
Program. Despite the recent increase in drug shortages, FDA has not
substantially changed the resources or priority it places on its
response to drug shortages. Although FDA recognizes the significant
public health consequences that can result from drug shortages, it has
not taken the important step of developing metrics that would help it
manage the Drug Shortage Program. Indeed, the agency does not maintain
data in a manner that would enhance its ability to understand trends
in the shortages that are, and are not, occurring. The agency has not
identified drug shortages as an area of strategic priority, and
generally does not track its own performance related to preventing or
mitigating the effects of drug shortages. Therefore, FDA cannot fully
understand the extent to which its actions are effective. FDA lacks a
systematic method to manage its complex workload related to drug
shortages--and to share this information among the many offices within
the agency whose efforts must be coordinated. Without sufficient data,
prioritization, or performance metrics, FDA cannot ensure that it is
doing all it can to protect the public health.
Matter for Congressional Consideration:
To strengthen FDA's ability to respond to drug shortages, Congress
should consider establishing a requirement for manufacturers to report
potential or actual supply disruptions to FDA. Such notification
requirements should call for manufacturers to notify FDA of any
changes, interruptions, or adjustments that could affect the supply of
their drugs. Congress may also wish to consider providing FDA with the
authority to seek civil monetary penalties or use other enforcement
mechanisms to ensure compliance with this requirement.
Recommendations for Executive Action:
To strengthen FDA's ability to protect the public health through its
response to drug shortages, we recommend that the Commissioner of FDA
take the following four actions:
* assess the resources allocated to the Drug Shortage Program to
determine whether reallocation is needed to improve the agency's
response to drug shortages;
* develop an information system that will enable the Drug Shortage
Program to manage its daily workload in a systematic manner, track
data about drug shortages--including their causes and FDA's response--
and share information across FDA offices regarding drugs that are in
short supply;
* ensure that FDA's strategic plan articulates goals and priorities
for maintaining the availability of all medically necessary drugs--
including generic drugs; and:
* develop results-oriented performance metrics to assess and quantify
the implementation of the agency's goals and FDA's response to drug
shortages.
Agency and Third-Party Comments and Our Evaluation:
In its comments on a draft of this report, HHS acknowledged that drug
shortages pose serious risks to public health and emphasized the
agency's position on addressing this challenge. HHS stated that it
supports legislation that would require manufacturers to report
potential or actual supply disruptions to FDA. In addition, HHS
outlined its intent to take actions that are consistent with our
recommendations. For example, it noted that it has plans to increase
the number of staff working in the Drug Shortage Program, and that it
has identified some potential performance metrics that it may use to
gauge the success of FDA's response to drug shortages. We believe that
such plans are an important first step toward enhancing the agency's
response to drug shortages.
HHS's comments also stated that FDA has developed a database to
analyze drug shortages in real time. As noted in our report, we
believe that the spreadsheet FDA refers to as a database will not
enable the agency to optimally manage drug shortage information on a
systematic basis, and we encourage the agency to implement our
recommendation to develop a more robust information system to manage
these data. In addition, HHS stated that FDA has prevented 137 drug
shortages from 2010 through September 2011. Our counts of prevented
drug shortages differ from FDA's because we consider a prevented
shortage of multiple versions of the same drug (for example, multiple
concentrations of the same drug) as one prevented shortage, whereas
FDA counted each separately. Thus for example, we reported 50
potential shortages avoided during the first half of 2011 in contrast
to FDA reporting 99.
HHS's comments also cited a number of actions that the Administration
has taken since receiving our draft report for review. Specifically,
while our draft report was at HHS for comment, the President issued an
Executive Order on October 31, 2011, that directs FDA to take steps
that are intended to support, enhance, and amplify the agency's
response to drug shortages.[Footnote 53] The order directed FDA to
expand its efforts to expedite reviews of applications that would help
to prevent or resolve shortages. FDA also issued a report summarizing
its approach to drug shortages, which includes a list of actions the
agency should take in order to strengthen its response to drug
shortages.[Footnote 54] HHS's Office of the Assistant Secretary for
Planning and Evaluation also issued a report summarizing the economic
factors that cause drug shortages.[Footnote 55] We are encouraged by
the Administration's response to this issue, and believe its
expeditious implementation of the recommendations included in our
report, as well as the executive order and FDA's report, will serve to
strengthen the agency's ability to prevent, alleviate, and resolve
drug shortages.
HHS's comments are reprinted in appendix III. We also provided UUDIS
with excerpts of the draft report related to the number of drug
shortages. We received technical comments from both HHS and UUDIS,
which we incorporated as appropriate.
As agreed with your offices, unless you publicly announce the contents
of this report earlier, we plan no further distribution until 30 days
from the report date. At that time, we will send copies to the
Commissioner of FDA and appropriate congressional committees. The
report also will be available at no charge on the GAO website at
[hyperlink, http://www.gao.gov].
If you or your staff have any questions about this report, please
contact me at (202) 512-7114 or crossem@gao.gov. Contact points for
our Offices of Congressional Relations and Public Affairs may be found
on the last page of this report. GAO staff who made key contributions
to this report are listed in appendix IV.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: FDA Criteria for Determining Whether a Drug Is Medically
Necessary:
FDA's Drug Shortage Program places the highest priority on responding
to shortages of medically necessary drugs, since such shortages have
the greatest potential to impact the public health. FDA defines a
medically necessary drug as any drug that is used to treat or prevent
a serious disease or medical condition for which there is no other
adequately available drug that is judged to be an appropriate
substitute.[Footnote 56] To determine whether a drug is medically
necessary for the purpose of prioritizing its response to drug
shortages, FDA's Drug Shortage Program requests the input of medical
officers in the Office of New Drugs (OND) who have relevant expertise
with the drug.[Footnote 57] Specifically, the Drug Shortage Program
asks OND medical officers to complete a form that requests information
about the drug and requests the official's judgment regarding whether
the drug meets the agency's criteria for medical necessity. FDA
officials told us that they ensure consistency in the process by
ensuring that each completed form is reviewed by three FDA officials
who have expertise with the drug before it is finalized and provided
to the Drug Shortage Program. In addition, FDA officials told us that
they sometimes consult with health professional organizations such as
the American Society of Health-System Pharmacists when determining
whether a drug is medically necessary.
The background questions listed on the form request information about
the drug, such as its trade name or generic name and the product's
formulation(s). It also includes questions about the manufacturer,
including its name, address, and phone number, and whether the drug is
available from more than one manufacturer. In addition to requesting
this background information about the drug, the form includes several
questions, the responses to which are used to determine whether the
drug meets the agency's definition of medically necessary. (See figure
5.)
Figure 5: Questions Included on FDA's Medical Necessity Determination
Form:
[Refer to PDF for image: illustration]
1. Is the product used to treat a serious disease or medical condition?
No:
Yes - Explain:
2. What are the labeled indications for this product?
3. Are there important off-label uses, such as those for a serious
medical condition?
(Please note that off-label uses can be considered medically
necessary.)
4. Are there generic forms of this product?
No:
Yes - Are there any special benefits/risks associated with the generic
product(s)?
5. Are there alternative products available?
No:
Yes - Please explain the risk(s) and benefit(s) of the alternative
product(s):
Please cite the trade name(s) and generic name(s).
6. From the above assessment, is this product medically necessary?
(Please note that this question refers only to the overall medical
necessity of the product(s), not whether the specific (manufacturer’s)
product in question is appropriate for continued administration to
patients.)
No:
Yes - Please state if this is only for specific indications:
7. Additional comments:
Source: Excerpted from FDA Medical Necessity Determination form.
[End of figure]
[End of section]
Appendix II: Summary of FDA's Response to 15 Selected Drug Shortages:
Based on our review of FDA's response to 15 drug shortages, we found
that the agency took multiple actions to address the causes of
shortages and to enhance the drugs' availability. Specifically, we
reviewed FDA's response to shortages involving 5 anti-infective drugs
(acyclovir, amikacin, cefotetan, clindamycin, and sulfamethoxazole-
trimethoprim), 5 oncology drugs (cisplatin, cytarabine, doxorubicin,
etoposide, and vincristine), and 5 anesthesia drugs (epinephrine,
neostigmine, propofol, thiopental, and succinylcholine). At the time
of these shortages, FDA determined that all 15 drugs involved with the
shortages we reviewed in detail were medically necessary.[Footnote 58]
Our analysis showed that FDA typically used two or more types of
actions to respond to each shortage, and for 8 of these shortages, the
agency responded with four or more types of actions. For example,
during the shortage of doxorubicin, an oncology drug, FDA used seven
types of actions to respond to the shortage, including providing
assistance to address manufacturing problems related to drug quality
issues and providing assistance to address importation delays for
active pharmaceutical ingredients or finished products. Our analysis
also showed that while FDA searched for a firm willing and able to
import a version of the drug in shortage not approved in the United
States during 7 of the 15 shortages we reviewed, the agency applied
its regulatory discretion regarding the importation of a version of
the drug that was not approved in the United States in order to
alleviate 1 shortage. Figure 6 displays FDA's response to each of the
15 drug shortages we reviewed.
Figure 6: Actions Taken by FDA in Response to Sterile Injectable Drug
Shortages That Were Reported Between January 2009 and June 2011, by
Drug Class and Name:
[Refer to PDF for image: illustrated table]
FDA Action: FDA offered assistance to manufacturers to prevent,
alleviate, or resolve the shortage;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Check];
Amikacin: [Check];
Cefotetan: [Check];
Clindamycin[A]: [Check];
Sulfamethoxazole trimethoprim: [Check];
Drug class and name, Oncology drugs:
Cisplatin: [Check];
Cytarabine: [Check];
Doxorubicin: [Check];
Etoposide: [Check];
Vincristine: [Check];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Check];
Neostigmine: [Check];
Propofol: [Check];
Succinylcholine: [Check];
Thiopental: [Check].
FDA Action: FDA notified other manufacturers to expect increased
demand or encouraged other manufacturers to increase production;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Check];
Amikacin: [Check];
Cefotetan: [Check];
Clindamycin[A]: [Check];
Sulfamethoxazole trimethoprim: [B];
Drug class and name, Oncology drugs:
Cisplatin: [Check];
Cytarabine: [Check];
Doxorubicin: [Check];
Etoposide: [Check];
Vincristine: [Check];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Check];
Neostigmine: [Check];
Propofol: [Check];
Succinylcholine: [Check];
Thiopental: [B].
FDA Action: FDA provided assistance to address manufacturing problems
related to drug quality issues;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Empty];
Amikacin: [Empty];
Cefotetan: [Empty];
Clindamycin[A]: [Check];
Sulfamethoxazole trimethoprim: [Check];
Drug class and name, Oncology drugs:
Cisplatin: [Check];
Cytarabine: [Check];
Doxorubicin: [Check];
Etoposide: [Empty];
Vincristine: [Empty];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Check];
Neostigmine: [Check];
Propofol: [Check];
Succinylcholine: [Empty];
Thiopental: [Empty].
FDA Action: FDA searched for a firm willing and able to import a
version of the drug in shortage not approved in the United States;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Empty];
Amikacin: [Check];
Cefotetan: [Empty];
Clindamycin[A]: [Empty];
Sulfamethoxazole trimethoprim: [Empty];
Drug class and name, Oncology drugs:
Cisplatin: [Check];
Cytarabine: [Check];
Doxorubicin: [Check];
Etoposide: [Check];
Vincristine: [Empty];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Empty];
Neostigmine: [Empty];
Propofol: [Check];
Succinylcholine: [Check];
Thiopental: [Empty].
FDA Action: At FDA’s discretion, a manufacturer imported a version of
the drug in shortage not approved in the United States;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Empty];
Amikacin: [Empty];
Cefotetan: [Empty];
Clindamycin[A]: [Empty];
Sulfamethoxazole trimethoprim:
Drug class and name, Oncology drugs:
Cisplatin: [Empty];
Cytarabine: [Empty];
Doxorubicin: [Empty];
Etoposide: [Empty];
Vincristine: [Empty];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Empty];
Neostigmine: [Empty];
Propofol: [Check];
Succinylcholine: [Empty];
Thiopental: [Empty].
FDA Action: FDA expedited its review of an application supplement or
abbreviated new drug application;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Empty];
Amikacin: [Check];
Cefotetan: [Check];
Clindamycin[A]: [Empty];
Sulfamethoxazole trimethoprim: [Empty];
Drug class and name, Oncology drugs:
Cisplatin: [Empty];
Cytarabine: [Empty];
Doxorubicin: [Check];
Etoposide: [Empty];
Vincristine: [Empty];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Empty];
Neostigmine: [Empty];
Propofol: [Check];
Succinylcholine: [Check];
Thiopental: [Empty].
FDA Action: At FDA’s discretion, a manufacturer continued to market a
drug despite labeling or quality issues;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Empty];
Amikacin: [Empty];
Cefotetan: [Empty];
Clindamycin[A]: [Empty];
Sulfamethoxazole trimethoprim: [Check];
Drug class and name, Oncology drugs:
Cisplatin: [Empty];
Cytarabine: [Check];
Doxorubicin: [Check];
Etoposide: [Empty];
Vincristine: [Empty];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Check];
Neostigmine: [Empty];
Propofol: [Check];
Succinylcholine:
Thiopental: [Empty].
FDA Action: FDA provided assistance to address importation delays for
active pharmaceutical ingredients or finished products;
Drug class and name, Anti-infective drugs:
Acyclovir[A]: [Empty];
Amikacin: [Empty];
Cefotetan: [Empty];
Clindamycin[A]: [Empty];
Sulfamethoxazole trimethoprim: [Empty];
Drug class and name, Oncology drugs:
Cisplatin: [Empty];
Cytarabine: [Check];
Doxorubicin: [Check];
Etoposide: [Empty];
Vincristine: [Empty];
Drug class and name, Anesthesia drugs:
Epinephrine[A]: [Empty];
Neostigmine: [Check];
Propofol: [Check];
Succinylcholine: [Check];
Thiopental: [Empty].
[Check]: Denotes FDA action.
[A] Agency officials told us that although all of these shortages involved medically necessary drugs, three did not meet the agency’s criteria for a shortage. While these three shortages did not meet FDA’s criteria, all shortages we reviewed in detail were identified by representatives from the
American Society of Anesthesiologists, American Society of Clinical Oncology, and the Infectious Diseases Society of America as recent shortages that had significant impact on patient care or public health.
[B] At the time of the shortage, this drug was produced by a single
manufacturer, therefore there were no other manufacturers that FDA
could notify of an expected increase in demand or to encourage
increased production.
Note: Not all potential FDA actions are relevant for every shortage.
For example, during a shortage caused by a disruption in the supply of
an active pharmaceutical ingredient, it would not be necessary for FDA
to provide assistance to address manufacturing problems.
[End of figure]
[End of section]
Appendix III: Comments from the Department of Health and Human
Services:
Department Of Health & Human Services:
Office Of The Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
November 3, 2011:
Marcia Crosse, Director:
Health Care:
U.S. Government Accountability Office:
441 G Street NW:
Washington, DC 20548:
Dear Ms. Crosse:
Attached are comments on the U.S. Government Accountability Office's
(GAO) draft report entitled, "Drug Shortages: FDA's Ability to Respond
Should Be Strengthened" (GAO-12116).
The Department appreciates the opportunity to review this report prior
to publication.
Sincerely,
Signed by:
Jim R. Esquea:
Assistant Secretary for Legislation:
Attachment:
[End of section]
General Comments Of The Department Of Health and Human Services (HHS)
On The Government Accountability Office's (GAO) Draft Report Entitled,
"Drug Shortages: FDA's Ability To Respond Should Be Strengthened" (GAO-
12-116):
The Department appreciates the opportunity to review and comment on
this draft report.
Over the last 5 years, drug shortages in the United States have
steadily and dramatically grown, tripling from 61 in 2005 to 178 in
2010. Since at least the founding of the Food and Drug
Administration's (FDA) drug shortage program in 1999, the agency has
been mindful of the hardships and adverse health consequences that
drug shortages impose on patients, and has taken an active and
responsive role in mitigating and preventing drug shortages. FDA has
worked relentlessly to avoid disruptions in patient care by preventing
and mitigating drug shortages, making tremendous contributions to the
lives of American patients and improving their healthcare outcomes.
Since 2010 through September 2011, FDA prevented 137 drug shortages.
Recognizing that drug shortages pose a serious and growing threat to
public health, on October 31, 2011, President Obama issued an
Executive Order, Reducing Prescription Drug Shortages. The Executive
Order acknowledges FDA's diligent efforts to prevent and mitigate drug
shortages, and emphasizes that the early disclosure of shortages is
extremely important to their prevention and mitigation. The
President's Executive Order supports, enhances, and amplifies FDA's
efforts and charges FDA to take the following actions:
* use all appropriate administrative tools to ensure that
manufacturers provide adequate advance notice of manufacturing
discontinuances that could lead to shortages of drugs that are life
supporting or life sustaining, or that prevent debilitating disease;
* take steps to expand its current efforts to expedite regulatory
reviews, including reviews of new drug suppliers, manufacturing sites,
and manufacturing changes, whenever it determines that expedited
review would help to avoid or mitigate existing or potential drug
shortages; and;
* communicate to the Department of Justice (DOJ) any findings that
shortages have led market participants to stockpile the affected drugs
or sell them at exorbitant prices so that DOJ may determine whether
these activities are lawful and take any appropriate enforcement
actions.[Footnote 1]
FDA appreciates the attention and visibility that this Executive Order
provides to the agency's ongoing work on drug shortages. As a
reflection of FDA's concern and attention regarding drug shortages,
and the high priority FDA places on this issue, in January 2011, the
agency began a review of medical product shortages in the four medical
product centers of the agency. Based on this review, FDA has released
a report, A Review of FDA's Approach to Medical Product Shortages,
that analyzes the problem and identifies the following findings:
* Of the 127 studied drug shortages in 2010-11, sterile injectables
accounted for the majority. The major therapeutic classes of drugs in
shortage were oncology drugs, antibiotics, and electrolyte/nutrition
drugs.
* The leading reasons for the shortages were problems at the
manufacturing facility, delays in manufacturing or shipping, and
active pharmaceutical ingredient shortages.
* Manufacturing quality problems that have resulted in shortages can
be serious, including findings of glass shards, metal filings, and
fungal or other contamination in products meant for injection into
patients.
* Sterile injectable drugs have unique manufacturing and market
features which make shortages of these products more likely to occur
and harder to prevent or mitigate.[Footnote 2]
The review also reveals that the most common FDA action to prevent a
drug shortage was expediting review of new manufacturing sites, new
suppliers, and specification changes, followed by exercising
regulatory flexibility and discretion. Once FDA is notified of a
shortage, the agency has many options to mitigate the drug shortage,
and in many cases, takes more than one action. In the shortages
studied, the agency's four most common actions were:
* asking other firms to increase production,
* working with manufacturers to identify ways to reduce the dangers of
products with quality issues,
* expediting review of regulatory submissions, and,
* exercising regulatory discretion regarding controlled importation of
similar products approved abroad but not approved in the United States.
Furthermore, in order to understand what is causing drug shortages and
to enable the evaluation of potential solutions, HHS conducted an
analysis of the underlying factors that lead to periods of shortage in
the prescription drug market.[Footnote 3] This report complements the
FDA's report on the current drug shortage problem.
No single or simple solution can resolve the problem of medical
product shortages. Consequently, efforts to address the problem must
be multifaceted, sustained over the long-term, and involve the
engagement of all parties involved in the manufacture and distribution
of these products. To contribute to such efforts, FDA has actively
explored and implemented measures within its purview to improve and
maximize its efforts toward the prevention and mitigation of drug
shortages:
* FDA created a drug shortages task force within its Center for Drug
Evaluation and Research (CDER) to enhance intra-center activities on
drug shortages.
* FDA created a dedicated recalls and shortages branch within CDER
that helps manage drug shortages.
* FDA's CDER developed a Drug Shortages Action Plan to enhance
communications with manufacturers and stakeholders, increase the
availability and usability of drug shortages information, and enhance
staffing and internal collaborations.[Footnote 4]
* The FDA Commissioner participated in a stakeholder meeting convened
on September 9, 2011 by the Department to discuss and explore
solutions to the drug shortages affecting patients in the United
States.[Footnote 5]
* FDA sponsored a public workshop on September 26, 2011 to provide
information for, and to gain additional insight from, professional
societies, patient advocates, industry, consumer groups, health care
professionals, researchers, and other interested persons about the
causes and impact of drug shortages, and possible strategies for
preventing and mitigating drug shortages.[Footnote 6]
* FDA developed a database to analyze the epidemiology of drug
shortages in real time. This database will be used to track all
current drug shortages, and will eventually also be populated with
data from past years. It will allow the agency to analyze trends in
drug shortages, as well as to assess its performance in mitigating and
preventing shortages, through the use of some potential metrics that
were included in the FDA report referred to earlier. FDA appreciates
GAO's comments on this database and will consider them as the agency
moves forward with implementation.
* In coordination with the President's Executive Order, FDA sent a
letter to manufacturers on October 31, 2011 reminding them of their
legal obligations, under certain circumstances, to notify FDA of the
discontinuation of any sole source drugs, and encouraging them to
voluntarily notify FDA of any disruptions that could lead to drug
shortages.[Footnote 7]
FDA is committed to ensuring that patients have access to safe and
effective medicines and our work to prevent and mitigate drug
shortages is no exception. FDA's Drug Shortage Program highlights this
commitment, and the agency anticipates its workload will increase as
we endeavor to enhance our ability to prevent and ease shortages. FDA
has started expanding its drug shortages workforce, and we look
forward to their help in tracking shortages, analyzing trends, and
establishing clear guidelines and procedures to enhance internal
collaborations and communications.
The Congress also has shown interest in drug shortages, and on
September 23, the House Committee on Energy and Commerce's
Subcommittee on Health held a hearing to examine the increase in drug
shortages. Bipartisan legislation (H.R. 2245 and S. 296) supported by
the Administration also has been introduced in Congress to address the
growing problem of drug shortages.
The steadily growing number of drug shortages and their effect on the
health of American patients compel all relevant stakeholders to seek
solutions, and FDA is committed to participating in robust and
effective collaboration to help resolve this critical problem. The
causes of drug shortages are extremely complex and have economic,
regulatory and legal underpinnings that will require the long-term
engagement and thinking of many relevant stakeholders, including
manufacturers and other participants along the drug supply chain,
regulators and legislators. Although many of the issues that
contribute to drug shortages lie outside of FDA's legal authorities,
FDA long has been, and will continue to be, vigorously engaged in
contributing to the resolution of this urgent public health concern.
Appendix III Footnotes:
[1] [hyperlink, http://www.whitehouse.gov/the-press-
office/2011/10/31/executive-order-reducing-prescription-drug-
shortages].
[2] [hyperlink,
http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm275051.htm].
[3] [hyperlink,
http://aspe.hhs.gov/sp/reports/2011/DrugShortages/ib.shtml].
[4] [hyperlink,
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277732.htm].
[5] [hyperlink,
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm271417.htm].
[6] [hyperlink,
http://www.fda.gov/downloads/Drugs/NewsEvents/UCM275801.pdf].
[7] [hyperlink,
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277675.htm].
[End of section]
Appendix IV: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114, crossem@gao.gov.
Acknowledgments:
In addition to the contact named above, Geraldine Redican-Bigott,
Assistant Director; Nick Bartine; Zhi Boon; Emily Goodman; Cathleen
Hamann; Yesook Merrill; Lisa Motley; and Patricia Roy made key
contributions to this report.
[End of section]
Related GAO Products:
Drug Pricing: Manufacturer Discounts in the 340B Program Offer
Benefits, but Federal Oversight Needs Improvement. [hyperlink,
http://www.gao.gov/products/GAO-11-836]. Washington, D.C.: September
23, 2011.
Drug Safety: FDA Faces Challenges Overseeing the Foreign Drug
Manufacturing Supply Chain. [hyperlink,
http://www.gao.gov/products/GAO-11-936T]. Washington, D.C.: September
14, 2011.
High-Risk Series: An Update. [hyperlink,
http://www.gao.gov/products/GAO-11-278]. Washington, D.C.: February
2011.
Food and Drug Administration: Response to Heparin Contamination Helped
Protect Public Health; Controls That Were Needed for Working With
External Entities Were Recently Added. [hyperlink,
http://www.gao.gov/products/GAO-11-95]. Washington, D.C.: October 29,
2010.
Food and Drug Administration: Opportunities Exist to Better Address
Management Challenges. [hyperlink,
http://www.gao.gov/products/GAO-10-279]. Washington, D.C.: February
19, 2010.
Food and Drug Administration: FDA Faces Challenges Meeting Its Growing
Medical Product Responsibilities and Should Develop Complete Estimates
of Its Resource Needs. [hyperlink,
http://www.gao.gov/products/GAO-09-581]. Washington, D.C.: June 19,
2009.
Human Capital: Key Principles for Effective Strategic Workforce
Planning. [hyperlink, http://www.gao.gov/products/GAO-04-39].
Washington, D.C.: December 11, 2003.
Standards for Internal Control in the Federal Government. [hyperlink,
http://www.gao.gov/products/GAO/AIMD-00-21.3.1] Washington, D.C.:
November 1999.
Agency Performance Plans: Examples of Practices That Can Improve
Usefulness to Decisionmakers. [hyperlink,
http://www.gao.gov/products/GAO/GGD/AIMD-99-69]. Washington, D.C.:
February 26, 1999.
Managing for Results: Critical Issues for Improving Federal Agencies'
Strategic Plans. [hyperlink,
http://www.gao.gov/products/GAO/GGD-97-180]. Washington, D.C.:
September 16, 1997.
[End of section]
Footnotes:
[1] ASHP posts information about drug shortages on its website. See
[hyperlink,
http://www.ashp.org/menu/PracticePolicy/ResourceCenters/DrugShortages.as
px].
[2] Because our analysis focused on shortages of prescription drugs,
we excluded from our analysis shortages of over-the-counter drugs,
biologics (including vaccines), medical devices, and orally-
administered vitamins, which UUDIS also tracks and includes in its
data.
[3] These 269 shortages represent 54 percent of the 495 shortages
reported during that time period.
[4] NDCs identify a drug's manufacturer, product name, route of
administration, dosage form, and package size, among other
information. One drug can have multiple NDCs associated with it. For
example, a drug made by one manufacturer in one strength but in three
package sizes would have three NDCs.
[5] Red Book is a compendium published by Thomson Reuters that
includes information about the characteristics of drug products.
[6] Specifically, the associations suggested, and we reviewed,
information about shortages for five anesthesia drugs (epinephrine,
neostigmine, propofol, thiopental, and succinylcholine), five oncology
drugs (cisplatin, cytarabine, doxorubicin, etoposide, and vincristine)
and five anti-infective drugs (acyclovir, amikacin, cefotetan,
clindamycin, and sulfamethoxazole-trimethoprim).
[7] Our work did not include a review of FDA's response to shortages
of biological products, such as vaccines.
[8] See GAO, Standards for Internal Control in the Federal Government,
[hyperlink, http://www.gao.gov/products/GAO/AIMD-00-21.3.1]
(Washington, D.C.: November 1999).
[9] The causes of drug shortages have been widely reported. See for
example, American Society of Health-System Pharmacists, ASHP
Guidelines on Managing Drug Product Shortages, American Journal of
Health-System Pharmacists, vol. 58, no. 1445-50 (2001): 26-30.
[10] An API is any component that is intended to provide
pharmacological activity or other direct effect in the diagnosis,
cure, mitigation, treatment, or prevention of disease. FDA defines
inactive ingredients as any component of a drug product other than the
API, such as materials that improve the appearance, stability, and
palatability of the product. See 21 C.F.R. § 210.3(b)(7), (8) (2011).
[11] See 21 C.F.R. § 7.40 (2011). Manufacturers may also decide to
recall a product for other reasons, such as errors in the product's
labeling.
[12] For example, we recently found evidence of drug shortages related
to stockpiling within the 340B Drug Pricing Program--a program through
which participating drug manufacturers give certain entities, such as
federally funded health centers and other federal grantees, access to
discounted prices on outpatient drugs. In some cases when the price of
a 340B drug dropped, providers with access to 340B's discounted prices
stockpiled a drug, resulting in shortages in the supply of that drug
for other providers. See GAO, Drug Pricing: Manufacturer Discounts in
the 340B Program Offer Benefits, but Federal Oversight Needs
Improvement, [hyperlink, http://www.gao.gov/products/GAO-11-836]
(Washington, D.C.: Sept. 23, 2011).
[13] We have previously reported on the challenges FDA faces in
overseeing an increasingly complex foreign drug manufacturing supply
chain. For example, see GAO, Drug Safety: FDA Faces Challenges
Overseeing the Foreign Drug Manufacturing Supply Chain, [hyperlink,
http://www.gao.gov/products/GAO-11-936T] (Washington, D.C.: Sept. 14,
2011).
[14] According to a 2011 American Hospital Association survey, over 80
percent of the 820 responding hospitals reported that patient
treatment had been delayed as a result of drug shortages. American
Hospital Association, AHA Survey on Drug Shortages (Washington, D.C.:
July 12, 2011).
[15] According to a report issued by the Institute for Safe Medication
Practices, about 25 percent of the 1,800 health care practitioners
that responded to its 2010 survey reported medication errors which
occurred as a result of a drug shortage. Institute for Safe Medication
Practices, Drug Shortages: National Survey Reveals High Level of
Frustration, Low Level of Safety (Horsham, Pa.: Sept. 23, 2010).
[16] According to AHA Survey on Drug Shortages, over 90 percent of 820
responding hospitals reported an increase in drug costs as a result of
drug shortages.
[17] A report issued by the Institute for Safe Medication Practices
noted that over half of the 549 hospitals that participated in its
2011 survey reported receiving daily solicitations from gray market
vendors for drugs that were in short supply. Institute for Safe
Medication Practices, Gray Market, Black Heart: Pharmaceutical Gray
Market Finds a Disturbing Niche During the Drug Shortage Crisis
(Horsham, Pa.: Aug. 25, 2011).
[18] Premier healthcare alliance, a group purchasing organization,
recently reported that 42 of its member hospitals recorded 1,745
offers to purchase drugs that were in short supply from the gray
market during a 2-week period at the beginning of 2011. Prices for
these products were, on average, 650 percent greater than Premier's
contract price, and ranged up to 4,533 percent greater than their
contract price. Premier healthcare alliance, Buyer Beware: Drug
Shortages and the Gray Market (Charlotte, N.C.: Aug. 16, 2011).
[19] The Institute for Safe Medication Practices reported in Gray
Market, Black Heart, that over 10 percent of the 549 hospitals that
participated in its 2011 survey were aware of product authenticity
issues, medication errors, or adverse drug reactions that were
associated with the use of products purchased from the gray market
during the last 2 years.
[20] Compounding pharmacies, like other pharmacies, are primarily
regulated by the states.
[21] 21 U.S.C. § 355.
[22] 21 U.S.C. § 355(j). The application for generic drugs is
abbreviated because FDA does not require sponsors to conduct, or
provide evidence from, clinical trials that are required of sponsors
of new drugs.
[23] 21 C.F.R. §§ 314.70, 314.97 (2011).
[24] These standards, referred to as current good manufacturing
practice regulations, provide a framework for a manufacturer to follow
to produce safe, pure, and high-quality drugs. See 21 C.F.R. parts 210-
211.
[25] A pharmaceutical equivalent is a drug product that is identical
in dosage form, API, and strength, and delivers an identical amount of
API over an identical dosing period. See 21 C.F.R. § 320.1(c) (2011).
[26] See, for example, GAO, Managing for Results: Critical Issues for
Improving Federal Agencies' Strategic Plans, [hyperlink,
http://www.gao.gov/products/GAO/GGD-97-180] (Washington, D.C.: Sept.
16, 1997).
[27] GAO, Food and Drug Administration: Opportunities Exist to Better
Address Management Challenges, [hyperlink,
http://www.gao.gov/products/GAO-10-279] (Washington, D.C.: Feb. 19,
2010).
[28] GAO, Agency Performance Plans: Examples of Practices That Can
Improve Usefulness to Decisionmakers, [hyperlink,
http://www.gao.gov/products/GAO/GGD/AIMD-99-69] (Washington, D.C.:
Feb. 26, 1999).
[29] GAO, Human Capital: Key Principles for Effective Strategic
Workforce Planning, [hyperlink, http://www.gao.gov/products/GAO-04-39]
(Washington, D.C.: Dec. 11, 2003).
[30] [hyperlink, http://www.gao.gov/products/GAO-10-279].
[31] GAO, High-Risk Series: An Update, [hyperlink,
http://www.gao.gov/products/GAO-11-278] (Washington, D.C.: February
2011).
[32] When tracking shortages, UUDIS groups together shortages of
multiple versions--for example, multiple concentrations--of the same
drug; the count of shortages reported therefore reflects this
grouping. The total number of shortages includes those that have been
resolved as well as active shortages. As of June 20, 2011, there were
230 active shortages, including some that were reported in prior years.
[33] We excluded 92 shortages from this analysis because UUDIS listed
these shortages as lasting zero days; the majority of these
represented manufacturers' decisions to discontinue their production
of a drug.
[34] We reviewed 269, or 54 percent, of the 495 total shortages
reported January 1, 2009, through June 20, 2011. These drug shortages
were those that UUDIS determined were critical.
[35] See 21 C.F.R. § 211.42(d) (2011).
[36] For example, FDA officials told us that if they were informed of
a shortage of a medically necessary and a non-medically necessary drug
on the same day, they would first respond to the medically necessary
drug shortage.
[37] As part of making this determination, FDA considers whether the
drug is being administered to patients for off-label uses--that is,
among other things, for conditions or patient populations for which
the drug was not approved or in a manner that is inconsistent with the
drug's FDA-approved label. Although FDA may not have approved a drug
to treat a particular condition or patient population, the agency is
aware that physicians may determine that prescribing a drug off label
constitutes good care for an individual patient, and therefore factors
off-label usage into its determination that a drug is medically
necessary for the purpose of prioritizing drug shortages. FDA also
considers drugs being studied in clinical trials in making its
determination. However, FDA does not consider patient inconvenience,
such as needing to take two tablets instead of one, as a reason to
classify a drug as medically necessary.
[38] According to FDA, the agency expedited its review of 375 ANDAs,
and 289 ANDA supplements from 2008 through July 2011 as a result of
potential or current drug shortages; the number of expedited reviews
exceeds the number of shortages reported during this period because
multiple applications or supplements may be expedited to alleviate a
shortage. FDA was unable to provide data regarding the length of time
it took for them to expedite their review of these applications,
including whether the reviews were completed prior to the resolution
of related shortages. The expedited reviews comprise a small portion
of the total number of applications pending FDA review as of July 30,
2011, which included 2,485 ANDAs, 6,235 ANDA supplements (which
includes 5,040 supplements requesting approval for manufacturing
changes and 1,195 supplements requesting approval for labeling
changes), and 894 NDA supplements requesting approval for
manufacturing changes.
[39] FDA officials were unable to provide data regarding the length of
time it took to review ANDAs and ANDA supplements that were expedited
as a result of a shortage.
[40] FDA officials told us that they do not typically consider
exercising regulatory discretion to respond to shortages of non-
medically necessary drugs because these drugs are, by definition, not
used to treat serious diseases or medical conditions, or other
clinically interchangeable versions of the drug are available.
[41] While these three shortages did not meet FDA's criteria, all of
the shortages we reviewed in detail were identified by representatives
from ASA, ASCO, and IDSA as recent shortages that had a significant
impact on patient care or public health.
[42] We grouped together shortages of multiple versions of the same
drug to identify the total number of shortages prevented. FDA
officials told us that the agency prevented 38 drug shortages in 2010
and 99 shortages in 2011, through June. However, these data
represented the number of individual drug products for which a
shortage had been averted, and did not group together multiple
versions--for example, multiple concentrations--of the same drug.
[43] See [hyperlink,
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm].
[44] See 21 U.S.C § 356c; 21 C.F.R. § 314.81(b)(3)(iii) (2011). To the
maximum extent possible, FDA is to distribute information on the
discontinuance of these products to appropriate physician and patient
organizations. FDA does not have the authority to enforce this
requirement, for example, by seeking civil monetary penalties.
[45] On October 31, 2011, the Commissioner of FDA sent a letter to all
drug manufacturers, reminding them of this requirement. See
[hyperlink,
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm277675.htm].
[46] Exec. Order No. 13,588, 76 Fed. Reg. 68,295 (Nov. 3, 2011).
[47] FDA officials told us that the best data that they could supply
us with would be copies of weekly e-mail messages, containing brief
narratives on the status of shortages in effect for the week in
question.
[48] For example, many shortages involve multiple manufacturers and
each may face multiple problems related to the production of the drug
before the shortage is resolved. During shortages, Drug Shortage
Program officials may need to communicate with officials from each
manufacturer to obtain information, as well as communicate with
different offices within FDA to share information related to the
agency’s response.
[49] In addition, we previously reported that, in response to a
potential shortage of heparin in 2008, FDA encouraged a manufacturer
to submit an ANDA, for which it had granted an expedited review.
However, despite the expedited designation, the approval process for
the application took 18 months, so this product was not available
until well after the supply of heparin had stabilized. See GAO, Food
and Drug Administration: Response to Heparin Contamination Helped
Protect Public Health; Controls That Were Needed for Working With
External Entities Were Recently Added, [hyperlink,
http://www.gao.gov/products/GAO-11-95] (Washington, D.C.: Oct. 29,
2010), 18.
[50] Agency officials estimated that, in addition to those staff
working in the Drug Shortage Program, about 25 full-time equivalent
employees provide some level of assistance in preventing, alleviating,
and resolving shortages—for example, by conducting determinations of
medical necessity and reviewing application supplements. However,
these additional staff also have other primary responsibilities.
[51] See GAO, Food and Drug Administration: FDA Faces Challenges
Meeting Its Growing Medical Product Responsibilities and Should
Develop Complete Estimates of Its Resource Needs, [hyperlink,
http://www.gao.gov/products/GAO-09-581] (Washington, D.C.: June 19,
2009).
[52] FDA has incorporated the concept of availability of drugs into
one of its strategic objectives; however, this objective is focused
solely on the processes FDA takes to ensure the availability of safe
and effective new drugs for the market. As such, it does not encompass
the availability of all drugs, including many medically necessary
drugs that are no longer manufactured by the company that marketed the
brand-name version of the drug and are thus available in generic form
only.
[53] Exec. Order No. 13,588, 76 Fed. Reg. 68,295 (Nov. 3, 2011).
[54] Food and Drug Administration, A Review of FDA’s Approach to
Medical Product Shortages (Silver Spring, Md.: Oct. 31, 2011).
[55] Office of the Assistant Secretary for Planning and Evaluation,
Economic Analysis of the Causes of Drug Shortages (Washington, D.C.:
Oct. 31, 2011).
[56] FDA does not consider patient inconvenience alone as a sufficient
reason to classify a product as medically necessary.
[57] FDA officials told us that if a drug is used to treat multiple
therapeutic conditions, they will request the input of multiple
medical officers, each of whom would have relevant expertise with the
drug.
[58] Twelve of these drugs are FDA-approved and 3-—epinephrine,
neostigmine, and thiopental-—were not FDA-approved as of October 2011.
According to FDA, the 3 unapproved drugs have been marketed in the
United States since before 1938, which is when the Federal Food, Drug,
and Cosmetic Act was enacted. The Act required FDA to approve new
drugs prior to their being marketed for sale. Because manufacturers of
these 3 drugs have not obtained FDA’s approval, the agency considers
the drugs to be illegally marketed. FDA estimates that there are as
many as several thousand unapproved drug products that are marketed
illegally. While unapproved drugs are subject to enforcement action,
FDA gives a higher priority to taking action against unapproved drugs
in certain categories, such as drugs with potential safety risks and
drugs that lack evidence of effectiveness. However, FDA officials told
us that some unapproved drugs may have medically necessary uses.
[End of section]
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